The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents
Identifieur interne : 000D15 ( Pmc/Corpus ); précédent : 000D14; suivant : 000D16The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents
Auteurs : Won-Suk Choi ; Khristine Kaith S. Lloren ; Yun Hee Baek ; Min-Suk SongSource :
- Clinical and Experimental Vaccine Research [ 2287-3651 ] ; 2017.
Abstract
Due to the increased frequency of interspecies transmission of avian influenza viruses, studies designed to identify the molecular determinants that could lead to an expansion of the host range have been increased. A variety of mouse-based mammalian-adaptation studies of avian influenza viruses have provided insight into the genetic alterations of various avian influenza subtypes that may contribute to the generation of a pandemic virus. To date, the studies have focused on avian influenza subtypes H5, H6, H7, H9, and H10 which have recently caused human infection. Although mice cannot fully reflect the course of human infection with avian influenza, these mouse studies can be a useful method for investigating potential mammalian adaptive markers against newly emerging avian influenza viruses. In addition, due to the lack of appropriate vaccines against the diverse emerging influenza viruses, the generation of mouse-adapted lethal variants could contribute to the development of effective vaccines or therapeutic agents. Within this review, we will summarize studies that have demonstrated adaptations of avian influenza viruses that result in an altered pathogenicity in mice which may suggest the potential application of mouse-lethal strains in the development of influenza vaccines and/or therapeutics in preclinical studies.
Url:
DOI: 10.7774/cevr.2017.6.2.83
PubMed: 28775972
PubMed Central: 5540968
Links to Exploration step
PMC:5540968Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents</title><author><name sortKey="Choi, Won Suk" sort="Choi, Won Suk" uniqKey="Choi W" first="Won-Suk" last="Choi">Won-Suk Choi</name><affiliation><nlm:aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</nlm:aff></affiliation></author><author><name sortKey="Lloren, Khristine Kaith S" sort="Lloren, Khristine Kaith S" uniqKey="Lloren K" first="Khristine Kaith S." last="Lloren">Khristine Kaith S. Lloren</name><affiliation><nlm:aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</nlm:aff></affiliation></author><author><name sortKey="Baek, Yun Hee" sort="Baek, Yun Hee" uniqKey="Baek Y" first="Yun Hee" last="Baek">Yun Hee Baek</name><affiliation><nlm:aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</nlm:aff></affiliation></author><author><name sortKey="Song, Min Suk" sort="Song, Min Suk" uniqKey="Song M" first="Min-Suk" last="Song">Min-Suk Song</name><affiliation><nlm:aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28775972</idno><idno type="pmc">5540968</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540968</idno><idno type="RBID">PMC:5540968</idno><idno type="doi">10.7774/cevr.2017.6.2.83</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000D15</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D15</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents</title><author><name sortKey="Choi, Won Suk" sort="Choi, Won Suk" uniqKey="Choi W" first="Won-Suk" last="Choi">Won-Suk Choi</name><affiliation><nlm:aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</nlm:aff></affiliation></author><author><name sortKey="Lloren, Khristine Kaith S" sort="Lloren, Khristine Kaith S" uniqKey="Lloren K" first="Khristine Kaith S." last="Lloren">Khristine Kaith S. Lloren</name><affiliation><nlm:aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</nlm:aff></affiliation></author><author><name sortKey="Baek, Yun Hee" sort="Baek, Yun Hee" uniqKey="Baek Y" first="Yun Hee" last="Baek">Yun Hee Baek</name><affiliation><nlm:aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</nlm:aff></affiliation></author><author><name sortKey="Song, Min Suk" sort="Song, Min Suk" uniqKey="Song M" first="Min-Suk" last="Song">Min-Suk Song</name><affiliation><nlm:aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</nlm:aff></affiliation></author></analytic><series><title level="j">Clinical and Experimental Vaccine Research</title><idno type="ISSN">2287-3651</idno><idno type="eISSN">2287-366X</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Due to the increased frequency of interspecies transmission of avian influenza viruses, studies designed to identify the molecular determinants that could lead to an expansion of the host range have been increased. A variety of mouse-based mammalian-adaptation studies of avian influenza viruses have provided insight into the genetic alterations of various avian influenza subtypes that may contribute to the generation of a pandemic virus. To date, the studies have focused on avian influenza subtypes H5, H6, H7, H9, and H10 which have recently caused human infection. Although mice cannot fully reflect the course of human infection with avian influenza, these mouse studies can be a useful method for investigating potential mammalian adaptive markers against newly emerging avian influenza viruses. In addition, due to the lack of appropriate vaccines against the diverse emerging influenza viruses, the generation of mouse-adapted lethal variants could contribute to the development of effective vaccines or therapeutic agents. Within this review, we will summarize studies that have demonstrated adaptations of avian influenza viruses that result in an altered pathogenicity in mice which may suggest the potential application of mouse-lethal strains in the development of influenza vaccines and/or therapeutics in preclinical studies.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hinshaw, Vs" uniqKey="Hinshaw V">VS Hinshaw</name></author><author><name sortKey="Wood, Jm" uniqKey="Wood J">JM Wood</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author><author><name sortKey="Deibel, R" uniqKey="Deibel R">R Deibel</name></author><author><name sortKey="Turner, B" uniqKey="Turner B">B Turner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author><author><name sortKey="Bean, Wj" uniqKey="Bean W">WJ Bean</name></author><author><name sortKey="Gorman, Ot" uniqKey="Gorman O">OT Gorman</name></author><author><name sortKey="Chambers, Tm" uniqKey="Chambers T">TM Chambers</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y Kawaoka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kilbourne, Ed" uniqKey="Kilbourne E">ED Kilbourne</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Gj" uniqKey="Smith G">GJ Smith</name></author><author><name sortKey="Vijaykrishna, D" uniqKey="Vijaykrishna D">D Vijaykrishna</name></author><author><name sortKey="Bahl, J" uniqKey="Bahl J">J Bahl</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Abdelwhab, Em" uniqKey="Abdelwhab E">EM Abdelwhab</name></author><author><name sortKey="Veits, J" uniqKey="Veits J">J Veits</name></author><author><name sortKey="Mettenleiter, Tc" uniqKey="Mettenleiter T">TC Mettenleiter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Yuan, H" uniqKey="Yuan H">H Yuan</name></author><author><name sortKey="Gao, R" uniqKey="Gao R">R Gao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, Q" uniqKey="Li Q">Q Li</name></author><author><name sortKey="Zhou, L" uniqKey="Zhou L">L Zhou</name></author><author><name sortKey="Zhou, M" uniqKey="Zhou M">M Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Malik Peiris, Js" uniqKey="Malik Peiris J">JS Malik Peiris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yuan, J" uniqKey="Yuan J">J Yuan</name></author><author><name sortKey="Zhang, L" uniqKey="Zhang L">L Zhang</name></author><author><name sortKey="Kan, X" uniqKey="Kan X">X Kan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Zf" uniqKey="Yang Z">ZF Yang</name></author><author><name sortKey="Mok, Ck" uniqKey="Mok C">CK Mok</name></author><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author><author><name sortKey="Zhong, Ns" uniqKey="Zhong N">NS Zhong</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Belser, Ja" uniqKey="Belser J">JA Belser</name></author><author><name sortKey="Katz, Jm" uniqKey="Katz J">JM Katz</name></author><author><name sortKey="Tumpey, Tm" uniqKey="Tumpey T">TM Tumpey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lowen, Ac" uniqKey="Lowen A">AC Lowen</name></author><author><name sortKey="Mubareka, S" uniqKey="Mubareka S">S Mubareka</name></author><author><name sortKey="Tumpey, Tm" uniqKey="Tumpey T">TM Tumpey</name></author><author><name sortKey="Garcia Sastre, A" uniqKey="Garcia Sastre A">A Garcia-Sastre</name></author><author><name sortKey="Palese, P" uniqKey="Palese P">P Palese</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lowen, Ac" uniqKey="Lowen A">AC Lowen</name></author><author><name sortKey="Steel, J" uniqKey="Steel J">J Steel</name></author><author><name sortKey="Mubareka, S" uniqKey="Mubareka S">S Mubareka</name></author><author><name sortKey="Palese, P" uniqKey="Palese P">P Palese</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kamal, Rp" uniqKey="Kamal R">RP Kamal</name></author><author><name sortKey="Katz, Jm" uniqKey="Katz J">JM Katz</name></author><author><name sortKey="York, Ia" uniqKey="York I">IA York</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, X" uniqKey="Lu X">X Lu</name></author><author><name sortKey="Tumpey, Tm" uniqKey="Tumpey T">TM Tumpey</name></author><author><name sortKey="Morken, T" uniqKey="Morken T">T Morken</name></author><author><name sortKey="Zaki, Sr" uniqKey="Zaki S">SR Zaki</name></author><author><name sortKey="Cox, Nj" uniqKey="Cox N">NJ Cox</name></author><author><name sortKey="Katz, Jm" uniqKey="Katz J">JM Katz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gambaryan, As" uniqKey="Gambaryan A">AS Gambaryan</name></author><author><name sortKey="Boravleva, Ey" uniqKey="Boravleva E">EY Boravleva</name></author><author><name sortKey="Matrosovich, Ty" uniqKey="Matrosovich T">TY Matrosovich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Qiu, M" uniqKey="Qiu M">M Qiu</name></author><author><name sortKey="Fang, F" uniqKey="Fang F">F Fang</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leneva, Ia" uniqKey="Leneva I">IA Leneva</name></author><author><name sortKey="Roberts, N" uniqKey="Roberts N">N Roberts</name></author><author><name sortKey="Govorkova, Ea" uniqKey="Govorkova E">EA Govorkova</name></author><author><name sortKey="Goloubeva, Og" uniqKey="Goloubeva O">OG Goloubeva</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smirnov, Ya" uniqKey="Smirnov Y">YA Smirnov</name></author><author><name sortKey="Lipatov, As" uniqKey="Lipatov A">AS Lipatov</name></author><author><name sortKey="Gitelman, Ak" uniqKey="Gitelman A">AK Gitelman</name></author><author><name sortKey="Claas, Ec" uniqKey="Claas E">EC Claas</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Govorkova, Ea" uniqKey="Govorkova E">EA Govorkova</name></author><author><name sortKey="Rehg, Je" uniqKey="Rehg J">JE Rehg</name></author><author><name sortKey="Krauss, S" uniqKey="Krauss S">S Krauss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hatta, M" uniqKey="Hatta M">M Hatta</name></author><author><name sortKey="Gao, P" uniqKey="Gao P">P Gao</name></author><author><name sortKey="Halfmann, P" uniqKey="Halfmann P">P Halfmann</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y Kawaoka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Subbarao, Ek" uniqKey="Subbarao E">EK Subbarao</name></author><author><name sortKey="London, W" uniqKey="London W">W London</name></author><author><name sortKey="Murphy, Br" uniqKey="Murphy B">BR Murphy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheng, K" uniqKey="Cheng K">K Cheng</name></author><author><name sortKey="Yu, Z" uniqKey="Yu Z">Z Yu</name></author><author><name sortKey="Chai, H" uniqKey="Chai H">H Chai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author><author><name sortKey="Ishaq, M" uniqKey="Ishaq M">M Ishaq</name></author><author><name sortKey="Prudence, M" uniqKey="Prudence M">M Prudence</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Song, Ms" uniqKey="Song M">MS Song</name></author><author><name sortKey="Pascua, Pn" uniqKey="Pascua P">PN Pascua</name></author><author><name sortKey="Lee, Jh" uniqKey="Lee J">JH Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Claas, Ec" uniqKey="Claas E">EC Claas</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Van Beek, R" uniqKey="Van Beek R">R van Beek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perrone, La" uniqKey="Perrone L">LA Perrone</name></author><author><name sortKey="Plowden, Jk" uniqKey="Plowden J">JK Plowden</name></author><author><name sortKey="Garcia Sastre, A" uniqKey="Garcia Sastre A">A Garcia-Sastre</name></author><author><name sortKey="Katz, Jm" uniqKey="Katz J">JM Katz</name></author><author><name sortKey="Tumpey, Tm" uniqKey="Tumpey T">TM Tumpey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mase, M" uniqKey="Mase M">M Mase</name></author><author><name sortKey="Tanimura, N" uniqKey="Tanimura N">N Tanimura</name></author><author><name sortKey="Imada, T" uniqKey="Imada T">T Imada</name></author><author><name sortKey="Okamatsu, M" uniqKey="Okamatsu M">M Okamatsu</name></author><author><name sortKey="Tsukamoto, K" uniqKey="Tsukamoto K">K Tsukamoto</name></author><author><name sortKey="Yamaguchi, S" uniqKey="Yamaguchi S">S Yamaguchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Min, Jy" uniqKey="Min J">JY Min</name></author><author><name sortKey="Santos, C" uniqKey="Santos C">C Santos</name></author><author><name sortKey="Fitch, A" uniqKey="Fitch A">A Fitch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hatta, M" uniqKey="Hatta M">M Hatta</name></author><author><name sortKey="Hatta, Y" uniqKey="Hatta Y">Y Hatta</name></author><author><name sortKey="Kim, Jh" uniqKey="Kim J">JH Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Long, Js" uniqKey="Long J">JS Long</name></author><author><name sortKey="Howard, Wa" uniqKey="Howard W">WA Howard</name></author><author><name sortKey="Nunez, A" uniqKey="Nunez A">A Nunez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Choi, Ws" uniqKey="Choi W">WS Choi</name></author><author><name sortKey="Baek, Yh" uniqKey="Baek Y">YH Baek</name></author><author><name sortKey="Kwon, Jj" uniqKey="Kwon J">JJ Kwon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, P" uniqKey="Han P">P Han</name></author><author><name sortKey="Hu, Y" uniqKey="Hu Y">Y Hu</name></author><author><name sortKey="Sun, W" uniqKey="Sun W">W Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smirnov, Ya" uniqKey="Smirnov Y">YA Smirnov</name></author><author><name sortKey="Lipatov, As" uniqKey="Lipatov A">AS Lipatov</name></author><author><name sortKey="Van Beek, R" uniqKey="Van Beek R">R Van Beek</name></author><author><name sortKey="Gitelman, Ak" uniqKey="Gitelman A">AK Gitelman</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Claas, Ec" uniqKey="Claas E">EC Claas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, H" uniqKey="Wu H">H Wu</name></author><author><name sortKey="Peng, X" uniqKey="Peng X">X Peng</name></author><author><name sortKey="Peng, X" uniqKey="Peng X">X Peng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Taft, As" uniqKey="Taft A">AS Taft</name></author><author><name sortKey="Ozawa, M" uniqKey="Ozawa M">M Ozawa</name></author><author><name sortKey="Fitch, A" uniqKey="Fitch A">A Fitch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Vries, E" uniqKey="De Vries E">E de Vries</name></author><author><name sortKey="Guo, H" uniqKey="Guo H">H Guo</name></author><author><name sortKey="Dai, M" uniqKey="Dai M">M Dai</name></author><author><name sortKey="Rottier, Pj" uniqKey="Rottier P">PJ Rottier</name></author><author><name sortKey="Van Kuppeveld, Fj" uniqKey="Van Kuppeveld F">FJ van Kuppeveld</name></author><author><name sortKey="De Haan, Ca" uniqKey="De Haan C">CA de Haan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dalby, Ar" uniqKey="Dalby A">AR Dalby</name></author><author><name sortKey="Iqbal, M" uniqKey="Iqbal M">M Iqbal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saito, T" uniqKey="Saito T">T Saito</name></author><author><name sortKey="Tanikawa, T" uniqKey="Tanikawa T">T Tanikawa</name></author><author><name sortKey="Uchida, Y" uniqKey="Uchida Y">Y Uchida</name></author><author><name sortKey="Takemae, N" uniqKey="Takemae N">N Takemae</name></author><author><name sortKey="Kanehira, K" uniqKey="Kanehira K">K Kanehira</name></author><author><name sortKey="Tsunekuni, R" uniqKey="Tsunekuni R">R Tsunekuni</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gu, M" uniqKey="Gu M">M Gu</name></author><author><name sortKey="Liu, W" uniqKey="Liu W">W Liu</name></author><author><name sortKey="Cao, Y" uniqKey="Cao Y">Y Cao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berhane, Y" uniqKey="Berhane Y">Y Berhane</name></author><author><name sortKey="Kobasa, D" uniqKey="Kobasa D">D Kobasa</name></author><author><name sortKey="Embury Hyatt, C" uniqKey="Embury Hyatt C">C Embury-Hyatt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Yi" uniqKey="Kim Y">YI Kim</name></author><author><name sortKey="Pascua, Pn" uniqKey="Pascua P">PN Pascua</name></author><author><name sortKey="Kwon, Hi" uniqKey="Kwon H">HI Kwon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pulit Penaloza, Ja" uniqKey="Pulit Penaloza J">JA Pulit-Penaloza</name></author><author><name sortKey="Sun, X" uniqKey="Sun X">X Sun</name></author><author><name sortKey="Creager, Hm" uniqKey="Creager H">HM Creager</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, Q" uniqKey="Li Q">Q Li</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author><author><name sortKey="Zhong, L" uniqKey="Zhong L">L Zhong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peng, X" uniqKey="Peng X">X Peng</name></author><author><name sortKey="Wu, H" uniqKey="Wu H">H Wu</name></author><author><name sortKey="Peng, X" uniqKey="Peng X">X Peng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, H" uniqKey="Wu H">H Wu</name></author><author><name sortKey="Peng, X" uniqKey="Peng X">X Peng</name></author><author><name sortKey="Peng, X" uniqKey="Peng X">X Peng</name></author><author><name sortKey="Wu, N" uniqKey="Wu N">N Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Capua, I" uniqKey="Capua I">I Capua</name></author><author><name sortKey="Mutinelli, F" uniqKey="Mutinelli F">F Mutinelli</name></author><author><name sortKey="Bozza, Ma" uniqKey="Bozza M">MA Bozza</name></author><author><name sortKey="Terregino, C" uniqKey="Terregino C">C Terregino</name></author><author><name sortKey="Cattoli, G" uniqKey="Cattoli G">G Cattoli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pasick, J" uniqKey="Pasick J">J Pasick</name></author><author><name sortKey="Berhane, Y" uniqKey="Berhane Y">Y Berhane</name></author><author><name sortKey="Hisanaga, T" uniqKey="Hisanaga T">T Hisanaga</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Den Berg, T" uniqKey="Van Den Berg T">T van den Berg</name></author><author><name sortKey="Houdart, P" uniqKey="Houdart P">P Houdart</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zanin, M" uniqKey="Zanin M">M Zanin</name></author><author><name sortKey="Kocer, Za" uniqKey="Kocer Z">ZA Kocer</name></author><author><name sortKey="Poulson, Rl" uniqKey="Poulson R">RL Poulson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Yi" uniqKey="Kim Y">YI Kim</name></author><author><name sortKey="Kim, Sw" uniqKey="Kim S">SW Kim</name></author><author><name sortKey="Si, Yj" uniqKey="Si Y">YJ Si</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Joseph, T" uniqKey="Joseph T">T Joseph</name></author><author><name sortKey="Mcauliffe, J" uniqKey="Mcauliffe J">J McAuliffe</name></author><author><name sortKey="Lu, B" uniqKey="Lu B">B Lu</name></author><author><name sortKey="Jin, H" uniqKey="Jin H">H Jin</name></author><author><name sortKey="Kemble, G" uniqKey="Kemble G">G Kemble</name></author><author><name sortKey="Subbarao, K" uniqKey="Subbarao K">K Subbarao</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="De Jong, Rm" uniqKey="De Jong R">RM de Jong</name></author><author><name sortKey="Stockhofe Zurwieden, N" uniqKey="Stockhofe Zurwieden N">N Stockhofe-Zurwieden</name></author><author><name sortKey="Verheij, Es" uniqKey="Verheij E">ES Verheij</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gabriel, G" uniqKey="Gabriel G">G Gabriel</name></author><author><name sortKey="Dauber, B" uniqKey="Dauber B">B Dauber</name></author><author><name sortKey="Wolff, T" uniqKey="Wolff T">T Wolff</name></author><author><name sortKey="Planz, O" uniqKey="Planz O">O Planz</name></author><author><name sortKey="Klenk, Hd" uniqKey="Klenk H">HD Klenk</name></author><author><name sortKey="Stech, J" uniqKey="Stech J">J Stech</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, Z" uniqKey="Yu Z">Z Yu</name></author><author><name sortKey="Sun, W" uniqKey="Sun W">W Sun</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Q" uniqKey="Chen Q">Q Chen</name></author><author><name sortKey="Yu, Z" uniqKey="Yu Z">Z Yu</name></author><author><name sortKey="Sun, W" uniqKey="Sun W">W Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, Y" uniqKey="Zhao Y">Y Zhao</name></author><author><name sortKey="Yu, Z" uniqKey="Yu Z">Z Yu</name></author><author><name sortKey="Liu, L" uniqKey="Liu L">L Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shinya, K" uniqKey="Shinya K">K Shinya</name></author><author><name sortKey="Watanabe, S" uniqKey="Watanabe S">S Watanabe</name></author><author><name sortKey="Ito, T" uniqKey="Ito T">T Ito</name></author><author><name sortKey="Kasai, N" uniqKey="Kasai N">N Kasai</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y Kawaoka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brown, Eg" uniqKey="Brown E">EG Brown</name></author><author><name sortKey="Liu, H" uniqKey="Liu H">H Liu</name></author><author><name sortKey="Kit, Lc" uniqKey="Kit L">LC Kit</name></author><author><name sortKey="Baird, S" uniqKey="Baird S">S Baird</name></author><author><name sortKey="Nesrallah, M" uniqKey="Nesrallah M">M Nesrallah</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Homme, Pj" uniqKey="Homme P">PJ Homme</name></author><author><name sortKey="Easterday, Bc" uniqKey="Easterday B">BC Easterday</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guo, Yj" uniqKey="Guo Y">YJ Guo</name></author><author><name sortKey="Krauss, S" uniqKey="Krauss S">S Krauss</name></author><author><name sortKey="Senne, Da" uniqKey="Senne D">DA Senne</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, M" uniqKey="Peiris M">M Peiris</name></author><author><name sortKey="Yuen, Ky" uniqKey="Yuen K">KY Yuen</name></author><author><name sortKey="Leung, Cw" uniqKey="Leung C">CW Leung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Khan, Su" uniqKey="Khan S">SU Khan</name></author><author><name sortKey="Anderson, Bd" uniqKey="Anderson B">BD Anderson</name></author><author><name sortKey="Heil, Gl" uniqKey="Heil G">GL Heil</name></author><author><name sortKey="Liang, S" uniqKey="Liang S">S Liang</name></author><author><name sortKey="Gray, Gc" uniqKey="Gray G">GC Gray</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y Guan</name></author><author><name sortKey="Shortridge, Kf" uniqKey="Shortridge K">KF Shortridge</name></author><author><name sortKey="Krauss, S" uniqKey="Krauss S">S Krauss</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, L" uniqKey="Yang L">L Yang</name></author><author><name sortKey="Zhu, W" uniqKey="Zhu W">W Zhu</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, A" uniqKey="Wu A">A Wu</name></author><author><name sortKey="Su, C" uniqKey="Su C">C Su</name></author><author><name sortKey="Wang, D" uniqKey="Wang D">D Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, D" uniqKey="Liu D">D Liu</name></author><author><name sortKey="Shi, W" uniqKey="Shi W">W Shi</name></author><author><name sortKey="Gao, Gf" uniqKey="Gao G">GF Gao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Yj" uniqKey="Lee Y">YJ Lee</name></author><author><name sortKey="Shin, Jy" uniqKey="Shin J">JY Shin</name></author><author><name sortKey="Song, Ms" uniqKey="Song M">MS Song</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Choi, Yk" uniqKey="Choi Y">YK Choi</name></author><author><name sortKey="Seo, Sh" uniqKey="Seo S">SH Seo</name></author><author><name sortKey="Kim, Ja" uniqKey="Kim J">JA Kim</name></author><author><name sortKey="Webby, Rj" uniqKey="Webby R">RJ Webby</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, H" uniqKey="Zhang H">H Zhang</name></author><author><name sortKey="Xu, B" uniqKey="Xu B">B Xu</name></author><author><name sortKey="Chen, Q" uniqKey="Chen Q">Q Chen</name></author><author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, R" uniqKey="Wu R">R Wu</name></author><author><name sortKey="Zhang, H" uniqKey="Zhang H">H Zhang</name></author><author><name sortKey="Yang, K" uniqKey="Yang K">K Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name></author><author><name sortKey="Hu, S" uniqKey="Hu S">S Hu</name></author><author><name sortKey="Li, Z" uniqKey="Li Z">Z Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, J" uniqKey="Wang J">J Wang</name></author><author><name sortKey="Sun, Y" uniqKey="Sun Y">Y Sun</name></author><author><name sortKey="Xu, Q" uniqKey="Xu Q">Q Xu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Q" uniqKey="Liu Q">Q Liu</name></author><author><name sortKey="Huang, J" uniqKey="Huang J">J Huang</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Q" uniqKey="Liu Q">Q Liu</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Huang, J" uniqKey="Huang J">J Huang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sang, X" uniqKey="Sang X">X Sang</name></author><author><name sortKey="Wang, A" uniqKey="Wang A">A Wang</name></author><author><name sortKey="Chai, T" uniqKey="Chai T">T Chai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, Kj" uniqKey="Park K">KJ Park</name></author><author><name sortKey="Song, Ms" uniqKey="Song M">MS Song</name></author><author><name sortKey="Kim, Eh" uniqKey="Kim E">EH Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, Q" uniqKey="Li Q">Q Li</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author><author><name sortKey="Sun, Z" uniqKey="Sun Z">Z Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, Z" uniqKey="Yu Z">Z Yu</name></author><author><name sortKey="Cheng, K" uniqKey="Cheng K">K Cheng</name></author><author><name sortKey="Xin, Y" uniqKey="Xin Y">Y Xin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tan, L" uniqKey="Tan L">L Tan</name></author><author><name sortKey="Su, S" uniqKey="Su S">S Su</name></author><author><name sortKey="Smith, Dk" uniqKey="Smith D">DK Smith</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yao, Y" uniqKey="Yao Y">Y Yao</name></author><author><name sortKey="Wang, H" uniqKey="Wang H">H Wang</name></author><author><name sortKey="Chen, Q" uniqKey="Chen Q">Q Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mei, K" uniqKey="Mei K">K Mei</name></author><author><name sortKey="Liu, G" uniqKey="Liu G">G Liu</name></author><author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tian, J" uniqKey="Tian J">J Tian</name></author><author><name sortKey="Qi, W" uniqKey="Qi W">W Qi</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Su, S" uniqKey="Su S">S Su</name></author><author><name sortKey="Bi, Y" uniqKey="Bi Y">Y Bi</name></author><author><name sortKey="Wong, G" uniqKey="Wong G">G Wong</name></author><author><name sortKey="Gray, Gc" uniqKey="Gray G">GC Gray</name></author><author><name sortKey="Gao, Gf" uniqKey="Gao G">GF Gao</name></author><author><name sortKey="Li, S" uniqKey="Li S">S Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, M" uniqKey="Liu M">M Liu</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author><author><name sortKey="Yuan, H" uniqKey="Yuan H">H Yuan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shi, W" uniqKey="Shi W">W Shi</name></author><author><name sortKey="Shi, Y" uniqKey="Shi Y">Y Shi</name></author><author><name sortKey="Wu, Y" uniqKey="Wu Y">Y Wu</name></author><author><name sortKey="Liu, D" uniqKey="Liu D">D Liu</name></author><author><name sortKey="Gao, Gf" uniqKey="Gao G">GF Gao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tzarum, N" uniqKey="Tzarum N">N Tzarum</name></author><author><name sortKey="De Vries, Rp" uniqKey="De Vries R">RP de Vries</name></author><author><name sortKey="Zhu, X" uniqKey="Zhu X">X Zhu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, G" uniqKey="Wang G">G Wang</name></author><author><name sortKey="Deng, G" uniqKey="Deng G">G Deng</name></author><author><name sortKey="Shi, J" uniqKey="Shi J">J Shi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nam, Jh" uniqKey="Nam J">JH Nam</name></author><author><name sortKey="Kim, Eh" uniqKey="Kim E">EH Kim</name></author><author><name sortKey="Song, D" uniqKey="Song D">D Song</name></author><author><name sortKey="Choi, Yk" uniqKey="Choi Y">YK Choi</name></author><author><name sortKey="Kim, Jk" uniqKey="Kim J">JK Kim</name></author><author><name sortKey="Poo, H" uniqKey="Poo H">H Poo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gillim Ross, L" uniqKey="Gillim Ross L">L Gillim-Ross</name></author><author><name sortKey="Santos, C" uniqKey="Santos C">C Santos</name></author><author><name sortKey="Chen, Z" uniqKey="Chen Z">Z Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Hr" uniqKey="Kim H">HR Kim</name></author><author><name sortKey="Lee, Yj" uniqKey="Lee Y">YJ Lee</name></author><author><name sortKey="Lee, Kk" uniqKey="Lee K">KK Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, H" uniqKey="Wu H">H Wu</name></author><author><name sortKey="Lu, R" uniqKey="Lu R">R Lu</name></author><author><name sortKey="Wu, X" uniqKey="Wu X">X Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, H" uniqKey="Wu H">H Wu</name></author><author><name sortKey="Lu, R" uniqKey="Lu R">R Lu</name></author><author><name sortKey="Wu, X" uniqKey="Wu X">X Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, M" uniqKey="Zhang M">M Zhang</name></author><author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name></author><author><name sortKey="Xu, K" uniqKey="Xu K">K Xu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Huang, L" uniqKey="Huang L">L Huang</name></author><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Francis, T" uniqKey="Francis T">T Francis</name></author><author><name sortKey="Magill, Tp" uniqKey="Magill T">TP Magill</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Yt" uniqKey="Lee Y">YT Lee</name></author><author><name sortKey="Kim, Kh" uniqKey="Kim K">KH Kim</name></author><author><name sortKey="Ko, Ej" uniqKey="Ko E">EJ Ko</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jang, Yh" uniqKey="Jang Y">YH Jang</name></author><author><name sortKey="Byun, Yh" uniqKey="Byun Y">YH Byun</name></author><author><name sortKey="Lee, Yj" uniqKey="Lee Y">YJ Lee</name></author><author><name sortKey="Lee, Yh" uniqKey="Lee Y">YH Lee</name></author><author><name sortKey="Lee, Kh" uniqKey="Lee K">KH Lee</name></author><author><name sortKey="Seong, Bl" uniqKey="Seong B">BL Seong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Sm" uniqKey="Kim S">SM Kim</name></author><author><name sortKey="Kim, Yi" uniqKey="Kim Y">YI Kim</name></author><author><name sortKey="Park, Sj" uniqKey="Park S">SJ Park</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Choi, Eh" uniqKey="Choi E">EH Choi</name></author><author><name sortKey="Song, Ms" uniqKey="Song M">MS Song</name></author><author><name sortKey="Park, Sj" uniqKey="Park S">SJ Park</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Song, Ms" uniqKey="Song M">MS Song</name></author><author><name sortKey="Moon, Hj" uniqKey="Moon H">HJ Moon</name></author><author><name sortKey="Kwon, Hi" uniqKey="Kwon H">HI Kwon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shim, Bs" uniqKey="Shim B">BS Shim</name></author><author><name sortKey="Choi, Yk" uniqKey="Choi Y">YK Choi</name></author><author><name sortKey="Yun, Ch" uniqKey="Yun C">CH Yun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, Ks" uniqKey="Park K">KS Park</name></author><author><name sortKey="Lee, J" uniqKey="Lee J">J Lee</name></author><author><name sortKey="Ahn, Ss" uniqKey="Ahn S">SS Ahn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, Ks" uniqKey="Park K">KS Park</name></author><author><name sortKey="Seo, Yb" uniqKey="Seo Y">YB Seo</name></author><author><name sortKey="Lee, Jy" uniqKey="Lee J">JY Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Eh" uniqKey="Kim E">EH Kim</name></author><author><name sortKey="Lee, Jh" uniqKey="Lee J">JH Lee</name></author><author><name sortKey="Pascua, Pn" uniqKey="Pascua P">PN Pascua</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takahashi, K" uniqKey="Takahashi K">K Takahashi</name></author><author><name sortKey="Moyo, P" uniqKey="Moyo P">P Moyo</name></author><author><name sortKey="Chigweshe, L" uniqKey="Chigweshe L">L Chigweshe</name></author><author><name sortKey="Chang, Wc" uniqKey="Chang W">WC Chang</name></author><author><name sortKey="White, Mr" uniqKey="White M">MR White</name></author><author><name sortKey="Hartshorn, Kl" uniqKey="Hartshorn K">KL Hartshorn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="D Agostini, C" uniqKey="D Agostini C">C D'Agostini</name></author><author><name sortKey="Palamara, At" uniqKey="Palamara A">AT Palamara</name></author><author><name sortKey="Favalli, C" uniqKey="Favalli C">C Favalli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sidwell, Rw" uniqKey="Sidwell R">RW Sidwell</name></author><author><name sortKey="Huffman, Jh" uniqKey="Huffman J">JH Huffman</name></author><author><name sortKey="Barnard, Dl" uniqKey="Barnard D">DL Barnard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Govorkova, Ea" uniqKey="Govorkova E">EA Govorkova</name></author><author><name sortKey="Leneva, Ia" uniqKey="Leneva I">IA Leneva</name></author><author><name sortKey="Goloubeva, Og" uniqKey="Goloubeva O">OG Goloubeva</name></author><author><name sortKey="Bush, K" uniqKey="Bush K">K Bush</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lipatov, As" uniqKey="Lipatov A">AS Lipatov</name></author><author><name sortKey="Gitelman, Ak" uniqKey="Gitelman A">AK Gitelman</name></author><author><name sortKey="Smirnov, Ya" uniqKey="Smirnov Y">YA Smirnov</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gitelman, Ak" uniqKey="Gitelman A">AK Gitelman</name></author><author><name sortKey="Kaverin, Nv" uniqKey="Kaverin N">NV Kaverin</name></author><author><name sortKey="Kharitonenkov, Ig" uniqKey="Kharitonenkov I">IG Kharitonenkov</name></author><author><name sortKey="Rudneva, Ia" uniqKey="Rudneva I">IA Rudneva</name></author><author><name sortKey="Zhdanov, Vm" uniqKey="Zhdanov V">VM Zhdanov</name></author></analytic></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Exp Vaccine Res</journal-id><journal-id journal-id-type="iso-abbrev">Clin Exp Vaccine Res</journal-id><journal-id journal-id-type="publisher-id">CEVR</journal-id><journal-title-group><journal-title>Clinical and Experimental Vaccine Research</journal-title></journal-title-group><issn pub-type="ppub">2287-3651</issn><issn pub-type="epub">2287-366X</issn><publisher><publisher-name>The Korean Vaccine Society</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28775972</article-id><article-id pub-id-type="pmc">5540968</article-id><article-id pub-id-type="doi">10.7774/cevr.2017.6.2.83</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title>The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-3253-4827</contrib-id><name><surname>Choi</surname><given-names>Won-Suk</given-names></name><xref ref-type="aff" rid="A1"></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-9858-9452</contrib-id><name><surname>Lloren</surname><given-names>Khristine Kaith S.</given-names></name><xref ref-type="aff" rid="A1"></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8453-4880</contrib-id><name><surname>Baek</surname><given-names>Yun Hee</given-names></name><xref ref-type="aff" rid="A1"></xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-6073-0783</contrib-id><name><surname>Song</surname><given-names>Min-Suk</given-names></name><xref ref-type="aff" rid="A1"></xref></contrib></contrib-group><aff id="A1">Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.</aff><author-notes><corresp>Corresponding author: Min-Suk Song, PhD. Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju 28644, Korea. Tel: +82-43-261-3778, Fax: +82-43-272-1603, <email>songminsuk@chungbuk.ac.kr</email></corresp></author-notes><pub-date pub-type="ppub"><month>7</month><year>2017</year></pub-date><pub-date pub-type="epub"><day>26</day><month>7</month><year>2017</year></pub-date><volume>6</volume><issue>2</issue><fpage>83</fpage><lpage>94</lpage><history><date date-type="received"><day>19</day><month>4</month><year>2017</year></date><date date-type="rev-recd"><day>03</day><month>5</month><year>2017</year></date><date date-type="accepted"><day>12</day><month>5</month><year>2017</year></date></history><permissions><copyright-statement>© Korean Vaccine Society.</copyright-statement><copyright-year>2017</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>Due to the increased frequency of interspecies transmission of avian influenza viruses, studies designed to identify the molecular determinants that could lead to an expansion of the host range have been increased. A variety of mouse-based mammalian-adaptation studies of avian influenza viruses have provided insight into the genetic alterations of various avian influenza subtypes that may contribute to the generation of a pandemic virus. To date, the studies have focused on avian influenza subtypes H5, H6, H7, H9, and H10 which have recently caused human infection. Although mice cannot fully reflect the course of human infection with avian influenza, these mouse studies can be a useful method for investigating potential mammalian adaptive markers against newly emerging avian influenza viruses. In addition, due to the lack of appropriate vaccines against the diverse emerging influenza viruses, the generation of mouse-adapted lethal variants could contribute to the development of effective vaccines or therapeutic agents. Within this review, we will summarize studies that have demonstrated adaptations of avian influenza viruses that result in an altered pathogenicity in mice which may suggest the potential application of mouse-lethal strains in the development of influenza vaccines and/or therapeutics in preclinical studies.</p></abstract><kwd-group><kwd>Influenza A virus</kwd><kwd>Mouse adaptation</kwd><kwd>Molecular determinant</kwd><kwd>Vaccination</kwd><kwd>Virulence</kwd><kwd>Serial passage</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution>National Research Foundation of Korea</institution><institution-id institution-id-type="CrossRef">http://dx.doi.org/10.13039/501100003725</institution-id></institution-wrap></funding-source><award-id>NRF-2015R1C1A1A01054160</award-id></award-group><award-group><funding-source><institution-wrap><institution>Ministry of Health and Welfare</institution><institution-id institution-id-type="CrossRef">http://dx.doi.org/10.13039/501100003625</institution-id></institution-wrap></funding-source><award-id>HI16C1032</award-id></award-group><award-group><funding-source><institution-wrap><institution>Chungbuk National University</institution><institution-id institution-id-type="CrossRef">http://dx.doi.org/10.13039/501100002461</institution-id></institution-wrap></funding-source></award-group></funding-group></article-meta></front><body><sec sec-type="intro"><title>Introduction</title><p>Most influenza A viruses, including 16 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes, have been found in migratory waterfowl, thus, waterfowl is believed to be a natural reservoir [<xref rid="B1" ref-type="bibr">1</xref><xref rid="B2" ref-type="bibr">2</xref>]. The influenza virus exhibits a restricted host species barrier in the avian host [<xref rid="B2" ref-type="bibr">2</xref>] and in general, infection to other mammals including humans with avian influenza virus is limited. A few subtypes have successfully transcended and developed a capacity to establish themselves in mammalian hosts, primarily based on the genetic nature of the RNA genome (e.g., eight segments and error-prone) which leads to mutations conferring the ability to cross the host barriers. There have been three worldwide flu pandemics in the 20th century (the Spanish flu [H1N1] in 1918; the Asian flu [H2N2] in 1957; the Hong Kong flu [H3N2] in 1968). Most of the causatives were reported to be originated from avian species and have caused pandemics after reassortment between the new avian influenza virus and the human influenza virus [<xref rid="B3" ref-type="bibr">3</xref>]. In June 2009, the World Health Organization (WHO) declared the novel influenza A (H1N1) virus as the first pandemic of the 21st century [<xref rid="B4" ref-type="bibr">4</xref>]. Molecular epidemiologic studies have shown that viruses prevalent in birds, pigs and humans have been reassorted in unknown events and then transmitted to humans [<xref rid="B5" ref-type="bibr">5</xref>]. Although the same subtype as the seasonal H1N1 virus was predominant at the time, most people under the age of 65 could be infected by the pandemic virus because they did not have immunity due to serologically differentiated immunogenicity [<xref rid="B6" ref-type="bibr">6</xref>]. The pandemics occurred when the novel subtypes of viruses or parts of genes (especially HA, NA) were introduced into humans through genetic reassortment. However, genetic reassortment, which is generally known to be the mechanism of past pandemics, is insufficient to account for the ability to overcome interspecies barriers. Before an influenza virus becomes established in new hosts, it must overcome host-specific factors, including the ability to adapt, survive, and thrive in another host; these adaptations are conferred as the result of genetic mutations and are thus also required for the virus to transcend the interspecies barriers. Although there is still little evidence of human-to-human transmission, a variety of avian influenza viruses (H5N1, H5N6, H6N1, H7N3, H7N7, H7N9, H9N2, and H10N8) have been infecting humans directly from avian species [<xref rid="B7" ref-type="bibr">7</xref><xref rid="B8" ref-type="bibr">8</xref><xref rid="B9" ref-type="bibr">9</xref><xref rid="B10" ref-type="bibr">10</xref><xref rid="B11" ref-type="bibr">11</xref><xref rid="B12" ref-type="bibr">12</xref>]. In particular, human infections caused by H5N1, H5N6, and H7N9 are rapidly increasing and mortality rates reach 30%–50% [<xref rid="B13" ref-type="bibr">13</xref>] indicating the urgent need for vaccines that effectively protect humans against these emerging viruses.</p><p>Recently, various animal models (e.g., mouse, ferret, and guinea pigs) have been established for studying influenza proliferation, pathogenesis, and transmissibility. Ferrets can experience influenza-like respiratory illnesses after infection similar to those observed in humans and can spread viruses through direct contact and aerosols. Therefore, the pathogenicity and transmissibility of influenza virus can be evaluated using the ferret model [<xref rid="B14" ref-type="bibr">14</xref>]. Unlike ferrets, guinea pigs do not cough or sneeze after influenza infection but have been successfully used to study viral transmission by direct contact and aerosol transmission models [<xref rid="B15" ref-type="bibr">15</xref><xref rid="B16" ref-type="bibr">16</xref>]. It was shown in the 1930s that swine and human influenza viruses can infect laboratory mice and have since been used extensively in influenza pathogenesis studies [<xref rid="B17" ref-type="bibr">17</xref>]. Although the mouse model may not fully mirror the clinical signs and behaviors of influenza infection in humans, there are numerous studies showing the suitability of mouse models (e.g., ability to study infections with various influenza viruses, low cost), and thus, it is still an important animal model in influenza research. Above all, laboratory mice play an important role in preclinical animal-model studies designed to evaluate the efficacy of newly developed vaccines and drugs, studies that are a priority given the growing incidence of human infections caused by novel avian influenza viruses and the urgent need to identify treatment and/or prevention options. However, the lack of appropriate mouse-lethal influenza viruses makes it difficult to assess the exact effects of vaccines or treatments, thus slowing development. Although some influenza viruses may exhibit high virulence without prior adaptation to the mouse [<xref rid="B18" ref-type="bibr">18</xref>], most viruses exhibit low susceptibility to mice since they are non-natural hosts of influenza. Therefore, an abundance of studies have been conducted to evaluate the efficacy of vaccines or inhibitors by first generating more virulent strains of low pathogenicity viruses by continuous passage in mouse lungs [<xref rid="B19" ref-type="bibr">19</xref><xref rid="B20" ref-type="bibr">20</xref><xref rid="B21" ref-type="bibr">21</xref><xref rid="B22" ref-type="bibr">22</xref>]. In addition, mouse-adaptation studies of a variety of avian influenza viruses have been used to discover the molecular determinants of influenza viruses, which are important for adapting to new hosts [<xref rid="B17" ref-type="bibr">17</xref>]. Key mutations, such as E627K in the PB2 gene which contributes to the ability of avian influenza viruses to: (1) infect to mammalian hosts (including humans) [<xref rid="B8" ref-type="bibr">8</xref><xref rid="B23" ref-type="bibr">23</xref><xref rid="B24" ref-type="bibr">24</xref><xref rid="B25" ref-type="bibr">25</xref>] and (2) exhibit high replicative properties, were identified via the mouse-adaptation approach [<xref rid="B26" ref-type="bibr">26</xref><xref rid="B27" ref-type="bibr">27</xref><xref rid="B28" ref-type="bibr">28</xref>]. Therefore, in this review, we will focus on avian influenza viruses isolated from birds or other mammalian hosts to determine what molecular determinants are identified through mouse-adaptation studies. Furthermore, we will summarize and discuss the significant use of laboratory mice for generating mouse-lethal viruses that may contribute to the development of vaccines or therapeutic agents.</p></sec><sec><title>Adaptation Using Avian Influenza Viruses in Mice</title><p>Since the first isolation of avian influenza virus in chickens (A/Brescia/1902 [H7N7]) in the beginning of 20th century, a variety of influenza ecology studies have shown that each type of influenza A viruses can be isolated from aquatic birds [<xref rid="B2" ref-type="bibr">2</xref>]. Some of the avian viruses caused previous pandemics and established in human. Furthermore, in 1997, the highly pathogenic avian influenza (HPAI) H5N1 virus infected humans in Hong Kong and caused severe diseases with high mortality [<xref rid="B29" ref-type="bibr">29</xref>]. Since the beginning of the 21st century, the number of molecular studies designed to identify changes capable of facilitating the interspecies transmission of avian influenza into human has dramatically increased. This increase is largely associated with studies aiming to adapt the virus in mammalian hosts, particularly mice. Recently, many avian influenza subtypes (e.g., H5, H6, H7, H9, and H10) have affected humans. Therefore, these subtypes of avian influenza viruses have been most commonly used to study their adaptation in mice and to determine what changes facilitate their ability to become highly virulent in the mammalian host.</p><sec><title>Mouse adaptation of avian H5 subtypes and the molecular determinants mediating virulence</title><p>From the time of the first human infection by the HPAI H5N1 virus (1997), until March 2017, there are 856 laboratory-reported cases of human infection and a 53% mortality rate [<xref rid="B13" ref-type="bibr">13</xref>]. Despite no evidence of sustained human-to-human transmission, the high rate of H5N1 interspecies transmission and pathogenicity has encouraged investigation into its potential to cause a pandemic. Even though not all HPAI H5N1 viruses show high virulence in mammalian hosts, generally, the H5N1 has able to replicate at high titer and been found to be lethal to mice prior to adaption [<xref rid="B18" ref-type="bibr">18</xref><xref rid="B30" ref-type="bibr">30</xref>]. The pathogenic characteristics of these HPAI H5N1 viruses did not require the generation of mouse-adapted virulent variants to preclinically evaluate the efficacy of new vaccines or therapeutic agents. Thus, most mouse-adaptation studies have been conducted to investigate the potential molecular determinants facilitating direct human infection by avian influenza viruses. Some HPAI H5N1 viruses which were avirulent in mice become highly virulent as early as in a single replication in mice when they acquire the E627K substitution within the PB2 gene [<xref rid="B27" ref-type="bibr">27</xref><xref rid="B31" ref-type="bibr">31</xref><xref rid="B32" ref-type="bibr">32</xref>]. The PB2-E627K mutation appeared as early as 4 days after inoculation and replaced E to K completely by day 6 after virus infection [<xref rid="B32" ref-type="bibr">32</xref>]. This mutation has been proposed to: (1) be associated with the high virulence of H5N1 virus in mice and (2) an enhancement in the viral replication efficiency in the mouse upper respiratory tract [<xref rid="B24" ref-type="bibr">24</xref><xref rid="B33" ref-type="bibr">33</xref>]. Further, the mutation was found more in H5N1 human isolates than avian [<xref rid="B34" ref-type="bibr">34</xref><xref rid="B35" ref-type="bibr">35</xref>] suggesting it is a mammalian-adaptive mutation. On the other hand, mouse-adaptation studies with HPAI H5N1 variant do not always lead to the acquisition of a virulence phenotype in the host. HPAI H5N1 human isolate (A/Vietnam/1194/04) with attenuated virulence in mice after passages in mice lung involved an E190G substitution within the HA gene resulting in an altered binding specificity [<xref rid="B36" ref-type="bibr">36</xref>].</p><p>Due to the high virulence of HPAI H5N1 virus in mice, it is unnecessary to generate mouse-adapted variants to evaluate new vaccines or therapeutic agents. However, the use of HPAI viruses should be conducted in an appropriate facility (i.e., higher than Biosafety Level 3 laboratory handling) by highly qualified individuals. This requirement limits the accessibility for researchers who are developing new prophylactic and therapeutic measures. Therefore, the generation of low pathogenic avian influenza (LPAI) H5 virus strains virulent in mice may confer a benefit through mitigation of some of these infection risks. Thus, studies have been conducted with LPAI H5N2 viruses adapted into mice by lung-to-lung sequential passages [<xref rid="B28" ref-type="bibr">28</xref><xref rid="B37" ref-type="bibr">37</xref>]. Unlike HPAI H5N1 viruses that are already lethal prior to adaptation and elevate the virulence in mice within a single passage [<xref rid="B27" ref-type="bibr">27</xref><xref rid="B31" ref-type="bibr">31</xref><xref rid="B32" ref-type="bibr">32</xref>], LPAI H5N2 viruses need multiple passages, (up to 23 serial lung-to-lung passages) to obtain highly virulent phenotypes in mice, suggesting that HPAI H5N1 has more intrinsic properties resulting in virulence in the new host. Several amino acid changes were observed in mouse-adapted H5N2 variants including PB2-E627K and PA-T97I that played a critical role in enhanced replication and virulence in mice [<xref rid="B28" ref-type="bibr">28</xref>]. Since the initial identification of PA-T97I mutation in association with enhanced polymerase activity, viral replication in vitro and/or virulence in mice, further studies have been conducted to observe other substitutions that relates with mammalian adaptation [<xref rid="B26" ref-type="bibr">26</xref><xref rid="B35" ref-type="bibr">35</xref><xref rid="B38" ref-type="bibr">38</xref><xref rid="B39" ref-type="bibr">39</xref>].</p><p>Despite the highly stable HA and NA combination (H5N1) HPAI virus which has been maintained for more than a decade [<xref rid="B40" ref-type="bibr">40</xref>], novel combinations of HPAI H5Nx viruses generated by natural reassortment have been widely circulating recently [<xref rid="B40" ref-type="bibr">40</xref><xref rid="B41" ref-type="bibr">41</xref><xref rid="B42" ref-type="bibr">42</xref>] since the first outbreak of HPAI H5N5 variant in 2008 [<xref rid="B43" ref-type="bibr">43</xref>]. In recent years, the HPAI H5N8 virus has spread worldwide and crossed from Eurasia to North America for the first time. This HPAI H5 virus had led to various H5Nx variants with genes native to North America, posing a great threat to humans. Although the H5Nx variants showed high pathogenicity to chickens [<xref rid="B44" ref-type="bibr">44</xref>], most viruses isolated from avian species have maintained low pathogenicity in mammalian hosts [<xref rid="B45" ref-type="bibr">45</xref><xref rid="B46" ref-type="bibr">46</xref>]. However, the emergence of novel H5 variants retaining characteristics of the HPAI form and spreading rapidly with massive genetic evolution increases the need for pandemic preparedness. In addition, studies reported that H5Nx variants rapidly acquire virulence phenotype after passages in mouse model [<xref rid="B35" ref-type="bibr">35</xref><xref rid="B47" ref-type="bibr">47</xref><xref rid="B48" ref-type="bibr">48</xref><xref rid="B49" ref-type="bibr">49</xref>]. Mouse-adaptation of HPAI H5N2 [<xref rid="B47" ref-type="bibr">47</xref><xref rid="B49" ref-type="bibr">49</xref>], H5N6 [<xref rid="B48" ref-type="bibr">48</xref>], and H5N8 [<xref rid="B35" ref-type="bibr">35</xref>] viruses have been investigated and found to involve a variety of substitutions, some of which are previously reported and some of which are newly identified via these studies. These substitutions may potentially be associated with the increased virulence in mammalian hosts. Of note, previously reported mutations (i.e., PB2-E627K, -Q591K, -D701N, and PA-T97I) also occurred in HPAI H5Nx viruses as observed in other viral strains after mouse adaptation [<xref rid="B17" ref-type="bibr">17</xref>]; a novel PB1-P708S mutation was also found in two H5N8 strains and shown to elicit increased viral replication and virulence in mice alone or synergistically with other virulence markers (PB2-E627K or -D701N) [<xref rid="B35" ref-type="bibr">35</xref>]. Interestingly, although most H5Nx viruses adapted in mice are clustered in clade 2.3.4.4 and/or shared more than 99% nucleotide sequence homology, they acquired the polymorphic and distinctive genetic markers (either PB2-E627K or PB2-Q591K/D701N) [<xref rid="B35" ref-type="bibr">35</xref><xref rid="B48" ref-type="bibr">48</xref><xref rid="B49" ref-type="bibr">49</xref>]. A single mutation such as PB2-E627K can confer a dramatic enhancement of virulence of HPAI H5 viruses in mice [<xref rid="B27" ref-type="bibr">27</xref><xref rid="B31" ref-type="bibr">31</xref>] but also the combination of other multiple mutations can also lead to an increase in virulence [<xref rid="B27" ref-type="bibr">27</xref><xref rid="B35" ref-type="bibr">35</xref>].</p></sec><sec><title>Mouse-adaptation of avian H7 subtypes and the molecular determinants mediating virulence</title><p>Although all of H7Nx subtypes have been isolated from wild birds, H7N1 [<xref rid="B50" ref-type="bibr">50</xref>], H7N3 [<xref rid="B51" ref-type="bibr">51</xref>], and H7N7 [<xref rid="B52" ref-type="bibr">52</xref>] subtypes have shown high pathogenicity to poultries. Recent studies demonstrated that many LPAI H7 viruses isolated from avian species in Eurasia and North America caused mortality in mice prior to adaptation [<xref rid="B53" ref-type="bibr">53</xref><xref rid="B54" ref-type="bibr">54</xref><xref rid="B55" ref-type="bibr">55</xref>], suggesting a potential public health risk. Furthermore, various avian H7 subtypes in combination with N2, N3, N7, and N9 have been introduced into humans through exposure to domestic poultry [<xref rid="B7" ref-type="bibr">7</xref>]. Particularly, there was a massive increase in human infections with LPAI H7N9 virus in China (more than 1,300 cases reported as of March 2017) with 30%-40% mortality. And most recently, the HPAI form of the H7N9 virus were found and has also infected humans [<xref rid="B56" ref-type="bibr">56</xref>]. The H7 avian subtype, together with H5, actively affects humans and possesses high potential to cause a pandemic.</p><p>Like HPAI H5N1, many H7 viruses, including LPAIs, are lethal to mice prior to adaptation [<xref rid="B53" ref-type="bibr">53</xref>]; many studies have demonstrated the adaptation of both HPAI [<xref rid="B57" ref-type="bibr">57</xref><xref rid="B58" ref-type="bibr">58</xref>] and LPAI [<xref rid="B59" ref-type="bibr">59</xref><xref rid="B60" ref-type="bibr">60</xref>] H7 viruses in mice to identify genetic determinants of virulence in a mammalian host. Both HPAI and LPAI H7 viruses acquired high virulence in three to seven passages in mice lungs [<xref rid="B57" ref-type="bibr">57</xref><xref rid="B59" ref-type="bibr">59</xref><xref rid="B60" ref-type="bibr">60</xref>]; this is slower than HPAI H5N1, but faster than LPAI H5N2 viruses. Moreover, all viruses classified as LPAI (including the H7N9 subtype) expanded their tissue tropism beyond the target organ (i.e., lungs) to brain, liver, spleen, kidney, and intestine after mouse adaptation [<xref rid="B59" ref-type="bibr">59</xref><xref rid="B60" ref-type="bibr">60</xref><xref rid="B61" ref-type="bibr">61</xref>]. Most studies of avian H7 mouse adaptation observed conserved PB2-E627K substitution [<xref rid="B57" ref-type="bibr">57</xref><xref rid="B59" ref-type="bibr">59</xref><xref rid="B60" ref-type="bibr">60</xref>]; this single change was sufficient to enhance the virulence of mouse-adapted H7 viruses. In addition, the PB2-E627K substitution was also observed in an equine H7N7 virus after mouse adaption and it is associated with an appreciable increase of virulence in mice [<xref rid="B62" ref-type="bibr">62</xref>]. A lethal mouse-adapted descendant SC35M originated from HPAI H7N7 (SC35) obtained several mutations (i.e., PB2-D701N, S714R, and NP-N319K) after mouse adaptation and combinations of these mutations synergistically increases viral polymerase activity, growth <italic>in vitro</italic> and virulence in mice [<xref rid="B58" ref-type="bibr">58</xref>]. Interestingly, lethal mouse-adapted H7N9 variants acquired none of the well-defined adaptive markers (e.g., PB2-E627K or -D701N), but instead obtained other 14 mutations including T97I and Q556R in PA gene [<xref rid="B61" ref-type="bibr">61</xref>] which was previously reported in other subtypes [<xref rid="B28" ref-type="bibr">28</xref><xref rid="B63" ref-type="bibr">63</xref>]. However, precise function of the mutations occurring in H7N9 needs to be verified in further studies.</p></sec><sec><title>Mouse adaptation of avian H9 subtypes and the molecular determinants mediating viral virulence</title><p>Since the first isolation of the avian influenza H9N2 subtype from turkeys in the Northern part of United States in 1966 [<xref rid="B64" ref-type="bibr">64</xref>], the subtype virus has been circulating among wild birds and domestic poultry in several Asian countries [<xref rid="B10" ref-type="bibr">10</xref><xref rid="B65" ref-type="bibr">65</xref>]. The influenza H9N2 subtype has also been identified in domestic mammals and humans [<xref rid="B65" ref-type="bibr">65</xref><xref rid="B66" ref-type="bibr">66</xref><xref rid="B67" ref-type="bibr">67</xref>] and has posed two major concerns: (1) the virus occasionally infects humans (although it is usually not fatal) and (2) the virus has donated its genetic material into the other avian influenza viruses such as HPAI H5N1 [<xref rid="B68" ref-type="bibr">68</xref>], H5Nx [<xref rid="B69" ref-type="bibr">69</xref>], H7N9 [<xref rid="B70" ref-type="bibr">70</xref>], and H10N8 [<xref rid="B71" ref-type="bibr">71</xref>], all of which cause major human infection and are suggested as candidates for the next pandemic.</p><p>Of all H9Nx subtypes, H9N2 has primarily been used to understand the mechanism of interspecies transmission and increased virulence in mammalian hosts (e.g., mice and ferrets) due to the prevalence of this subtype and its repeated introduction into humans [<xref rid="B67" ref-type="bibr">67</xref>]. In general, H9N2 influenza viruses isolated from avian hosts demonstrate no disease or mild disease activity in mice, although they have been shown to replicate in mouse lungs [<xref rid="B72" ref-type="bibr">72</xref><xref rid="B73" ref-type="bibr">73</xref><xref rid="B74" ref-type="bibr">74</xref>]. Therefore, the generation of lethal mouse-adapted variants may further contribute to the field's ability to evaluate the efficacy of the new vaccines and therapeutic agents against H9N2 influenza virus. Abundant mouse-adaptation studies have demonstrated the ability to identify strains with increased virulence in mice [<xref rid="B75" ref-type="bibr">75</xref><xref rid="B76" ref-type="bibr">76</xref><xref rid="B77" ref-type="bibr">77</xref><xref rid="B78" ref-type="bibr">78</xref><xref rid="B79" ref-type="bibr">79</xref><xref rid="B80" ref-type="bibr">80</xref><xref rid="B81" ref-type="bibr">81</xref>]. Like the HPAI H5 and H7 viruses that rapidly adapted to mice and exhibit high virulence (<xref ref-type="table" rid="T1">Table 1</xref>), most avian H9N2 subtypes rapidly acquired high virulence within 8 serial passages in mice lungs (<xref ref-type="table" rid="T1">Table 1</xref>). It should be noted, however, that there has been no evidence reported suggesting that the avian H9N2 virus has evolved into a highly pathogenic form. Moreover, some mouse-adapted H9N2 variants were able to replicate in peripheral organs other than respiratory tissues, an attribute typically observed in HPAI viruses in mice [<xref rid="B75" ref-type="bibr">75</xref><xref rid="B76" ref-type="bibr">76</xref>]. This suggests the presence of intrinsic genetic properties that facilitate the ability of the virus to rapidly adapt and become highly virulent in mammalian hosts like the HPAIs. During mouse adaptation, most H9N2 viruses rapidly obtain the mammalian-adaptive mutation PB2-E627K which has been also found in pandemic viruses and human isolates, and this mutation has been shown to play a critical role in enhancing virulence in mice [<xref rid="B75" ref-type="bibr">75</xref><xref rid="B76" ref-type="bibr">76</xref><xref rid="B77" ref-type="bibr">77</xref><xref rid="B80" ref-type="bibr">80</xref><xref rid="B81" ref-type="bibr">81</xref>]. It was previously demonstrated that, in H9N2 viruses, the artificially conferred PB2-E627K mutation dramatically increased virulence without prior adaptation in mammalian hosts [<xref rid="B80" ref-type="bibr">80</xref><xref rid="B87" ref-type="bibr">87</xref>]. In addition, other substitutions (i.e., PB2-F404L, -M147L, HA-N313D, and -N496S) contributed to enhanced virulence in mice and were associated with increased activity of viral polymerase, replication, or enhanced receptor binding [<xref rid="B77" ref-type="bibr">77</xref><xref rid="B78" ref-type="bibr">78</xref><xref rid="B80" ref-type="bibr">80</xref>].</p></sec><sec><title>Mouse adaptation of other avian subtypes and the molecular determinants in viral virulence</title><p>A variety of avian influenza strains are widely circulating in China and some occasionally infects humans [<xref rid="B88" ref-type="bibr">88</xref>]. Novel LPAI strains (H6N1 and H10N8) have recently emerged in humans and H10N8 has been reported to have infect three humans and caused two deaths [<xref rid="B89" ref-type="bibr">89</xref><xref rid="B90" ref-type="bibr">90</xref>]. Similar to the H7N9 virus, H10N8 was also reassorted from the H10 and N8 genes that originated from wild birds with the internal gene backbone of H9N2 AIVs [<xref rid="B71" ref-type="bibr">71</xref>]. Furthermore, because the H10N8 virus, like the H7N9 virus, causes an asymptomatic infection in poultry, it is difficult for people to recognize the virus even if the chicken is infected. As a result, people have more chance to become infected with the virus that exists in the poultries. Interestingly, H6 virus isolated from humans possesses a unique combination of four key residues in the receptor binding site that have not been previously observed in human or avian influenza viruses [<xref rid="B91" ref-type="bibr">91</xref>] and some avian H6 strains were transmittable between guinea pigs by direct contact [<xref rid="B92" ref-type="bibr">92</xref>]. Therefore, the mechanism of avian-to-human interspecies transmission of the viruses needs to be addressed and new vaccines may need to be developed as a means of preparing for a potential pandemic.</p><p>Although some H6 subtype strains showed high virulence in mice [<xref rid="B93" ref-type="bibr">93</xref><xref rid="B94" ref-type="bibr">94</xref>], avian-isolated H6 viruses are generally associated with mild-disease signs in mice [<xref rid="B85" ref-type="bibr">85</xref><xref rid="B92" ref-type="bibr">92</xref><xref rid="B94" ref-type="bibr">94</xref><xref rid="B95" ref-type="bibr">95</xref>]. Avian H10 subtype influenza viruses also led to only mild-to-moderate disease signs in mice [<xref rid="B96" ref-type="bibr">96</xref><xref rid="B97" ref-type="bibr">97</xref><xref rid="B98" ref-type="bibr">98</xref>]; one of the H10N8 human isolates, however, was highly virulent in mice [<xref rid="B99" ref-type="bibr">99</xref>]. Thus, the generation of lethal mouse-adapted H6 or H10 variants will be beneficial to evaluate the efficacy of the new vaccines and therapeutic agents. Several studies on the adaptation of avian influenza H6 and H10 viruses in mice have been reported [<xref rid="B38" ref-type="bibr">38</xref><xref rid="B83" ref-type="bibr">83</xref><xref rid="B84" ref-type="bibr">84</xref><xref rid="B85" ref-type="bibr">85</xref><xref rid="B86" ref-type="bibr">86</xref>]. All of the LPAI viruses adapted to mice acquired high virulence in mice (<xref ref-type="table" rid="T1">Table 1</xref>). Some mouse-adapted H6 variants, from wildtype strains with limited replication capacity in the lungs of infected mice, did display expanded tissue tropism to brain, spleen, or kidney following adaptation [<xref rid="B83" ref-type="bibr">83</xref><xref rid="B85" ref-type="bibr">85</xref>]. The significant enhancement of virulence of all H6 and H10 viruses were observed within eight serial lung-to-lung passages and associated with the conserved PB2-E627K mutation that is commonly observed in the other subtypes of avian influenza viruses after mouse adaptation (<xref ref-type="table" rid="T1">Table 1</xref>). One of the H10N8 human isolates which resulted in death possessed the PB2-E627K mutation and displayed high virulence in mice [<xref rid="B99" ref-type="bibr">99</xref>]. Apart from the PB2-E627K substitution, PA-T97I was observed in one H6 and one H10 strain [<xref rid="B38" ref-type="bibr">38</xref><xref rid="B83" ref-type="bibr">83</xref>].</p></sec></sec><sec><title>Evaluation of Protective Efficacy of Vaccines and Therapeutics by Challenging Mouse-Adapted Avian Influenza Viruses</title><p>Mouse-adaptation studies using human-originating strains of the influenza virus have been performed for more than 80 years [<xref rid="B17" ref-type="bibr">17</xref>]. Some mouse-adapted strains including A/Puerto Rico/8/1934(H1N1) (PR8) [<xref rid="B100" ref-type="bibr">100</xref>] have been widely used in various studies designed to (1) evaluate the efficacy of vaccines and therapeutics, (2) investigate host-virus interactions, and (3) identify immune-mediated mechanisms directed against influenza virus infection. Despite an established understanding of the mouse-specific pathogenesis and immunology of previously identified mouse-adapted strains, there remains a lack of knowledge of the immunogenicity and pathogenicity of recently emerging viruses in human (e.g., H5, H7, and H9). Therefore, the development and characterization of lethal mouse-adapted viruses that may adequately reflect the immunogenic and pathologic properties of these emerging viruses would help fill a substantial knowledge gap. In response to this need, there have been an abundance of studies designed to evaluate the effect of new vaccines and therapeutics and to investigate immunologic functions by using mouse-adapted avian influenza viruses.</p><p>Vaccination is one of the most effective and cost-effective interventions to prevent mortality and reduce morbidity associated with the influenza virus. However, the conventional inactivated/live-attenuated vaccines generate immunity only to specific strains and thus, need to be updated annually. Moreover, a recent increase in human infections with novel emerging viruses including avian influenza cannot be protected by conventional vaccines. Thus, universal vaccines designed to be more broadly reactive to various influenza strains and vaccines immunogenic to the specific emerging viruses are being developed [<xref rid="B101" ref-type="bibr">101</xref>]. Although the major purpose of mouse-adaptation studies with avian influenza were to investigate the molecular determinants altering virulence of avian virus in mammalian hosts, abundant studies have demonstrated the protective efficacy of various intervention approaches using the lethal mouse-adapted avian influenza viruses in mouse model [<xref rid="B102" ref-type="bibr">102</xref><xref rid="B103" ref-type="bibr">103</xref><xref rid="B104" ref-type="bibr">104</xref><xref rid="B105" ref-type="bibr">105</xref><xref rid="B106" ref-type="bibr">106</xref><xref rid="B107" ref-type="bibr">107</xref>]. Since a mouse-adapted H5N2 virus was originated from LPAI H5N2 [<xref rid="B28" ref-type="bibr">28</xref>] and exhibited high lethality in mice, it can therefore be used in BL-2 facility which makes it accessible and usable by more researchers interested in evaluating the efficacy of newly developing vaccines. There have been studies suggesting that a number of M2e-based vaccine candidates produce neutralizing antibodies that more broadly protect immunized mice from lethal mouse-adapted H5N2 [<xref rid="B28" ref-type="bibr">28</xref>] and H9N2 [<xref rid="B81" ref-type="bibr">81</xref>] challenges [<xref rid="B106" ref-type="bibr">106</xref><xref rid="B107" ref-type="bibr">107</xref><xref rid="B108" ref-type="bibr">108</xref><xref rid="B109" ref-type="bibr">109</xref>]. In addition, the mouse-adapted H5N2 virus also exhibited varying levels of lethality when mice were immunized with various vaccine candidates, suggesting an ability to identify effective candidates in the cold-adapted and NS1-truncated live-attenuated vaccine studies [<xref rid="B102" ref-type="bibr">102</xref><xref rid="B104" ref-type="bibr">104</xref>]. A DNA-vaccine in which the HA and NA genes obtained from avian H9N2 virus was used to immunize mice using electroporation was evaluated for its ability to convey protection by challenging lethal H9N2 virus generated by mouse adaptation [<xref rid="B20" ref-type="bibr">20</xref>].</p><p>The protective efficacy of therapeutic agents inhibiting influenza growth has been abundantly evaluated in mice by challenging with lethal mouse-adapted human influenza viruses [<xref rid="B21" ref-type="bibr">21</xref><xref rid="B110" ref-type="bibr">110</xref><xref rid="B111" ref-type="bibr">111</xref><xref rid="B112" ref-type="bibr">112</xref>]. Due to the high lethality of HPAI H5N1 virus in mice, the wild type virus has been used to evaluate the protective efficacy of therapeutic agents against this virus [<xref rid="B21" ref-type="bibr">21</xref><xref rid="B113" ref-type="bibr">113</xref>]. However, for strains of avian influenza virus with low levels of virulence in mice (e.g., H9N2—which is also suggested as a pandemic potential), it would be beneficial to develop a virulent phenotype in mice in order to evaluate the efficacy of drug candidates against this subtype [<xref rid="B21" ref-type="bibr">21</xref><xref rid="B113" ref-type="bibr">113</xref>].</p></sec><sec sec-type="conclusions"><title>Conclusion</title><p>There are limitations to using adapted variants since, after multiple passages in mice; they may occasionally acquire an antigenicity that is distinct from wild type virus [<xref rid="B37" ref-type="bibr">37</xref><xref rid="B114" ref-type="bibr">114</xref><xref rid="B115" ref-type="bibr">115</xref>] meaning that they may represent an inappropriate lethal challenge model. For this reason, the antigenicity of mouse-adapted variant (compared to wild type) should be verified before the challenge experiment. The adaptation of avian influenza potentially generates variants with a virulent phenotype in humans, although mostly are attenuated. The aim of mouse-adaptation studies of most avian influenza is to better characterize the mechanism of genetic evolution in the mammalian host, which may potentially cause the next pandemic. However, genetic mutations identified from mouse-adaptation studies may be independent of their enhanced virulence in mice, since some mutations may occur during proliferation in laboratory cells or by other causes. However, based on data obtained from a vast amount of studies, we highlight that a number of mutations that occur commonly in mice have been identified through adaptation in mice, and some of these mutations also occur when avian influenza viruses infect humans. In addition, it was predicted that the number of passages needed to cause pathogenicity in mice is a subtype-dependent or dependent on the characteristics of HP/LPAI. For instance, some LPAI viruses can induce extra-pulmonary infection in mice after mouse adaptation. Therefore, it is considered that the avian virus may have low pathogenic potential in chickens, but cause high pathogenicity in mammalian host following adaptation.</p><p>Although cases of human infection caused by HPAI H5N1 decreased by 92% in 2016 [<xref rid="B116" ref-type="bibr">116</xref>] compared to 2015 (10 vs. 136 cases, respectively), human infection with novel HPAI H5N6 variants has been increasing in China since 2013 and 16 cases (including six deaths) have been recently reported as of April 2017 [<xref rid="B13" ref-type="bibr">13</xref>]. Due to the elevated pandemic potential of the H5Nx variants, the recently generated mouse-adapted HPAI H5Nx variants of which wild type viruses exhibit mild-to-moderate virulence in mice [<xref rid="B35" ref-type="bibr">35</xref><xref rid="B47" ref-type="bibr">47</xref><xref rid="B48" ref-type="bibr">48</xref><xref rid="B49" ref-type="bibr">49</xref>] will facilitate the evaluation of the efficacy of vaccines directed against H5Nx variants. Taken together, mouse-adaptation studies not only provide a comprehensive understanding of the evolution of avian influenza virus in mammalian hosts, but also can be used as an excellent tool to assess the efficacy of newly developing vaccines when new emerging viruses are introduced and thus, will play an important role in influenza research.</p></sec></body><back><fn-group><fn fn-type="COI-statement"><p>No potential conflict of interest relevant to this article was reported.</p></fn><fn fn-type="supported-by"><p>This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning [NRF-2015R1C1A1A01054160 to MSS] and by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI16C1032] and by a research grant of the Chungbuk National University in 2015.</p></fn></fn-group><ref-list><ref id="B1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hinshaw</surname><given-names>VS</given-names></name><name><surname>Wood</surname><given-names>JM</given-names></name><name><surname>Webster</surname><given-names>RG</given-names></name><name><surname>Deibel</surname><given-names>R</given-names></name><name><surname>Turner</surname><given-names>B</given-names></name></person-group><article-title>Circulation of influenza viruses and paramyxoviruses in waterfowl originating from two different areas of North America</article-title><source>Bull World Health Organ</source><year>1985</year><volume>63</volume><fpage>711</fpage><lpage>719</lpage><pub-id pub-id-type="pmid">3878741</pub-id></element-citation></ref><ref id="B2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Webster</surname><given-names>RG</given-names></name><name><surname>Bean</surname><given-names>WJ</given-names></name><name><surname>Gorman</surname><given-names>OT</given-names></name><name><surname>Chambers</surname><given-names>TM</given-names></name><name><surname>Kawaoka</surname><given-names>Y</given-names></name></person-group><article-title>Evolution and ecology of influenza A viruses</article-title><source>Microbiol Rev</source><year>1992</year><volume>56</volume><fpage>152</fpage><lpage>179</lpage><pub-id pub-id-type="pmid">1579108</pub-id></element-citation></ref><ref id="B3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kilbourne</surname><given-names>ED</given-names></name></person-group><article-title>Influenza pandemics of the 20th century</article-title><source>Emerg Infect Dis</source><year>2006</year><volume>12</volume><fpage>9</fpage><lpage>14</lpage><pub-id pub-id-type="pmid">16494710</pub-id></element-citation></ref><ref id="B4"><label>4</label><element-citation publication-type="book"><collab>World Health Organization</collab><source>World now at the start of 2009 influenza pandemic [Internet]</source><publisher-loc>Geneva</publisher-loc><publisher-name>World Health Organization</publisher-name><year>2009</year><date-in-citation content-type="access-date">cited 2017 May 1</date-in-citation><comment>Available from: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/">http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/</ext-link></comment></element-citation></ref><ref id="B5"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smith</surname><given-names>GJ</given-names></name><name><surname>Vijaykrishna</surname><given-names>D</given-names></name><name><surname>Bahl</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic</article-title><source>Nature</source><year>2009</year><volume>459</volume><fpage>1122</fpage><lpage>1125</lpage><pub-id pub-id-type="pmid">19516283</pub-id></element-citation></ref><ref id="B6"><label>6</label><element-citation publication-type="journal"><collab>Centers for Disease Control and Prevention (CDC)</collab><article-title>Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine</article-title><source>MMWR Morb Mortal Wkly Rep</source><year>2009</year><volume>58</volume><fpage>521</fpage><lpage>524</lpage><pub-id pub-id-type="pmid">19478718</pub-id></element-citation></ref><ref id="B7"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Abdelwhab</surname><given-names>EM</given-names></name><name><surname>Veits</surname><given-names>J</given-names></name><name><surname>Mettenleiter</surname><given-names>TC</given-names></name></person-group><article-title>Prevalence and control of H7 avian influenza viruses in birds and humans</article-title><source>Epidemiol Infect</source><year>2014</year><volume>142</volume><fpage>896</fpage><lpage>920</lpage><pub-id pub-id-type="pmid">24423384</pub-id></element-citation></ref><ref id="B8"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>H</given-names></name><name><surname>Yuan</surname><given-names>H</given-names></name><name><surname>Gao</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study</article-title><source>Lancet</source><year>2014</year><volume>383</volume><fpage>714</fpage><lpage>721</lpage><pub-id pub-id-type="pmid">24507376</pub-id></element-citation></ref><ref id="B9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>Q</given-names></name><name><surname>Zhou</surname><given-names>L</given-names></name><name><surname>Zhou</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Epidemiology of human infections with avian influenza A(H7N9) virus in China</article-title><source>N Engl J Med</source><year>2014</year><volume>370</volume><fpage>520</fpage><lpage>532</lpage><pub-id pub-id-type="pmid">23614499</pub-id></element-citation></ref><ref id="B10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Malik Peiris</surname><given-names>JS</given-names></name></person-group><article-title>Avian influenza viruses in humans</article-title><source>Rev Sci Tech</source><year>2009</year><volume>28</volume><fpage>161</fpage><lpage>173</lpage><pub-id pub-id-type="pmid">19618624</pub-id></element-citation></ref><ref id="B11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yuan</surname><given-names>J</given-names></name><name><surname>Zhang</surname><given-names>L</given-names></name><name><surname>Kan</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Origin and molecular characteristics of a novel 2013 avian influenza A(H6N1) virus causing human infection in Taiwan</article-title><source>Clin Infect Dis</source><year>2013</year><volume>57</volume><fpage>1367</fpage><lpage>1368</lpage><pub-id pub-id-type="pmid">23881153</pub-id></element-citation></ref><ref id="B12"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname><given-names>ZF</given-names></name><name><surname>Mok</surname><given-names>CK</given-names></name><name><surname>Peiris</surname><given-names>JS</given-names></name><name><surname>Zhong</surname><given-names>NS</given-names></name></person-group><article-title>Human infection with a novel avian influenza A(H5N6) virus</article-title><source>N Engl J Med</source><year>2015</year><volume>373</volume><fpage>487</fpage><lpage>489</lpage></element-citation></ref><ref id="B13"><label>13</label><element-citation publication-type="book"><collab>World Health Organization</collab><source>Avian influenza weekly update number 579 [Internet]</source><publisher-loc>Geneva</publisher-loc><publisher-name>World Health Organization</publisher-name><year>2017</year><date-in-citation content-type="access-date">cited 2017 May 1</date-in-citation><comment>Available from: <ext-link ext-link-type="uri" xlink:href="http://www.wpro.who.int/emerging_diseases/AvianInfluenza/en/">http://www.wpro.who.int/emerging_diseases/AvianInfluenza/en/</ext-link></comment></element-citation></ref><ref id="B14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Belser</surname><given-names>JA</given-names></name><name><surname>Katz</surname><given-names>JM</given-names></name><name><surname>Tumpey</surname><given-names>TM</given-names></name></person-group><article-title>The ferret as a model organism to study influenza A virus infection</article-title><source>Dis Model Mech</source><year>2011</year><volume>4</volume><fpage>575</fpage><lpage>579</lpage><pub-id pub-id-type="pmid">21810904</pub-id></element-citation></ref><ref id="B15"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lowen</surname><given-names>AC</given-names></name><name><surname>Mubareka</surname><given-names>S</given-names></name><name><surname>Tumpey</surname><given-names>TM</given-names></name><name><surname>Garcia-Sastre</surname><given-names>A</given-names></name><name><surname>Palese</surname><given-names>P</given-names></name></person-group><article-title>The guinea pig as a transmission model for human influenza viruses</article-title><source>Proc Natl Acad Sci U S A</source><year>2006</year><volume>103</volume><fpage>9988</fpage><lpage>9992</lpage><pub-id pub-id-type="pmid">16785447</pub-id></element-citation></ref><ref id="B16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lowen</surname><given-names>AC</given-names></name><name><surname>Steel</surname><given-names>J</given-names></name><name><surname>Mubareka</surname><given-names>S</given-names></name><name><surname>Palese</surname><given-names>P</given-names></name></person-group><article-title>High temperature (30 degrees C) blocks aerosol but not contact transmission of influenza virus</article-title><source>J Virol</source><year>2008</year><volume>82</volume><fpage>5650</fpage><lpage>5652</lpage><pub-id pub-id-type="pmid">18367530</pub-id></element-citation></ref><ref id="B17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kamal</surname><given-names>RP</given-names></name><name><surname>Katz</surname><given-names>JM</given-names></name><name><surname>York</surname><given-names>IA</given-names></name></person-group><article-title>Molecular determinants of influenza virus pathogenesis in mice</article-title><source>Curr Top Microbiol Immunol</source><year>2014</year><volume>385</volume><fpage>243</fpage><lpage>274</lpage><pub-id pub-id-type="pmid">25038937</pub-id></element-citation></ref><ref id="B18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lu</surname><given-names>X</given-names></name><name><surname>Tumpey</surname><given-names>TM</given-names></name><name><surname>Morken</surname><given-names>T</given-names></name><name><surname>Zaki</surname><given-names>SR</given-names></name><name><surname>Cox</surname><given-names>NJ</given-names></name><name><surname>Katz</surname><given-names>JM</given-names></name></person-group><article-title>A mouse model for the evaluation of pathogenesis and immunity to influenza A (H5N1) viruses isolated from humans</article-title><source>J Virol</source><year>1999</year><volume>73</volume><fpage>5903</fpage><lpage>5911</lpage><pub-id pub-id-type="pmid">10364342</pub-id></element-citation></ref><ref id="B19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gambaryan</surname><given-names>AS</given-names></name><name><surname>Boravleva</surname><given-names>EY</given-names></name><name><surname>Matrosovich</surname><given-names>TY</given-names></name><etal></etal></person-group><article-title>Polymer-bound 6′ sialyl-N-acetyllactosamine protects mice infected by influenza virus</article-title><source>Antiviral Res</source><year>2005</year><volume>68</volume><fpage>116</fpage><lpage>123</lpage><pub-id pub-id-type="pmid">16214231</pub-id></element-citation></ref><ref id="B20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Qiu</surname><given-names>M</given-names></name><name><surname>Fang</surname><given-names>F</given-names></name><name><surname>Chen</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Protection against avian influenza H9N2 virus challenge by immunization with hemagglutinin- or neuraminidase-expressing DNA in BALB/c mice</article-title><source>Biochem Biophys Res Commun</source><year>2006</year><volume>343</volume><fpage>1124</fpage><lpage>1131</lpage><pub-id pub-id-type="pmid">16580631</pub-id></element-citation></ref><ref id="B21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leneva</surname><given-names>IA</given-names></name><name><surname>Roberts</surname><given-names>N</given-names></name><name><surname>Govorkova</surname><given-names>EA</given-names></name><name><surname>Goloubeva</surname><given-names>OG</given-names></name><name><surname>Webster</surname><given-names>RG</given-names></name></person-group><article-title>The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses</article-title><source>Antiviral Res</source><year>2000</year><volume>48</volume><fpage>101</fpage><lpage>115</lpage><pub-id pub-id-type="pmid">11114412</pub-id></element-citation></ref><ref id="B22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smirnov</surname><given-names>YA</given-names></name><name><surname>Lipatov</surname><given-names>AS</given-names></name><name><surname>Gitelman</surname><given-names>AK</given-names></name><name><surname>Claas</surname><given-names>EC</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name></person-group><article-title>Prevention and treatment of bronchopneumonia in mice caused by mouse-adapted variant of avian H5N2 influenza A virus using monoclonal antibody against conserved epitope in the HA stem region</article-title><source>Arch Virol</source><year>2000</year><volume>145</volume><fpage>1733</fpage><lpage>1741</lpage><pub-id pub-id-type="pmid">11003481</pub-id></element-citation></ref><ref id="B23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Govorkova</surname><given-names>EA</given-names></name><name><surname>Rehg</surname><given-names>JE</given-names></name><name><surname>Krauss</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Lethality to ferrets of H5N1 influenza viruses isolated from humans and poultry in 2004</article-title><source>J Virol</source><year>2005</year><volume>79</volume><fpage>2191</fpage><lpage>2198</lpage><pub-id pub-id-type="pmid">15681421</pub-id></element-citation></ref><ref id="B24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hatta</surname><given-names>M</given-names></name><name><surname>Gao</surname><given-names>P</given-names></name><name><surname>Halfmann</surname><given-names>P</given-names></name><name><surname>Kawaoka</surname><given-names>Y</given-names></name></person-group><article-title>Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses</article-title><source>Science</source><year>2001</year><volume>293</volume><fpage>1840</fpage><lpage>1842</lpage><pub-id pub-id-type="pmid">11546875</pub-id></element-citation></ref><ref id="B25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Subbarao</surname><given-names>EK</given-names></name><name><surname>London</surname><given-names>W</given-names></name><name><surname>Murphy</surname><given-names>BR</given-names></name></person-group><article-title>A single amino acid in the PB2 gene of influenza A virus is a determinant of host range</article-title><source>J Virol</source><year>1993</year><volume>67</volume><fpage>1761</fpage><lpage>1764</lpage><pub-id pub-id-type="pmid">8445709</pub-id></element-citation></ref><ref id="B26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cheng</surname><given-names>K</given-names></name><name><surname>Yu</surname><given-names>Z</given-names></name><name><surname>Chai</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>PB2-E627K and PA-T97I substitutions enhance polymerase activity and confer a virulent phenotype to an H6N1 avian influenza virus in mice</article-title><source>Virology</source><year>2014</year><volume>468-470</volume><fpage>207</fpage><lpage>213</lpage><pub-id pub-id-type="pmid">25194918</pub-id></element-citation></ref><ref id="B27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>J</given-names></name><name><surname>Ishaq</surname><given-names>M</given-names></name><name><surname>Prudence</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Single mutation at the amino acid position 627 of PB2 that leads to increased virulence of an H5N1 avian influenza virus during adaptation in mice can be compensated by multiple mutations at other sites of PB2</article-title><source>Virus Res</source><year>2009</year><volume>144</volume><fpage>123</fpage><lpage>129</lpage><pub-id pub-id-type="pmid">19393699</pub-id></element-citation></ref><ref id="B28"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Song</surname><given-names>MS</given-names></name><name><surname>Pascua</surname><given-names>PN</given-names></name><name><surname>Lee</surname><given-names>JH</given-names></name><etal></etal></person-group><article-title>The polymerase acidic protein gene of influenza a virus contributes to pathogenicity in a mouse model</article-title><source>J Virol</source><year>2009</year><volume>83</volume><fpage>12325</fpage><lpage>12335</lpage><pub-id pub-id-type="pmid">19793828</pub-id></element-citation></ref><ref id="B29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Claas</surname><given-names>EC</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>van Beek</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus</article-title><source>Lancet</source><year>1998</year><volume>351</volume><fpage>472</fpage><lpage>477</lpage><pub-id pub-id-type="pmid">9482438</pub-id></element-citation></ref><ref id="B30"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Perrone</surname><given-names>LA</given-names></name><name><surname>Plowden</surname><given-names>JK</given-names></name><name><surname>Garcia-Sastre</surname><given-names>A</given-names></name><name><surname>Katz</surname><given-names>JM</given-names></name><name><surname>Tumpey</surname><given-names>TM</given-names></name></person-group><article-title>H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice</article-title><source>PLoS Pathog</source><year>2008</year><volume>4</volume><fpage>e1000115</fpage><pub-id pub-id-type="pmid">18670648</pub-id></element-citation></ref><ref id="B31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mase</surname><given-names>M</given-names></name><name><surname>Tanimura</surname><given-names>N</given-names></name><name><surname>Imada</surname><given-names>T</given-names></name><name><surname>Okamatsu</surname><given-names>M</given-names></name><name><surname>Tsukamoto</surname><given-names>K</given-names></name><name><surname>Yamaguchi</surname><given-names>S</given-names></name></person-group><article-title>Recent H5N1 avian influenza A virus increases rapidly in virulence to mice after a single passage in mice</article-title><source>J Gen Virol</source><year>2006</year><volume>87</volume><issue>Pt 12</issue><fpage>3655</fpage><lpage>3659</lpage><pub-id pub-id-type="pmid">17098982</pub-id></element-citation></ref><ref id="B32"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Min</surname><given-names>JY</given-names></name><name><surname>Santos</surname><given-names>C</given-names></name><name><surname>Fitch</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Mammalian adaptation in the PB2 gene of avian H5N1 influenza virus</article-title><source>J Virol</source><year>2013</year><volume>87</volume><fpage>10884</fpage><lpage>10888</lpage><pub-id pub-id-type="pmid">23864613</pub-id></element-citation></ref><ref id="B33"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hatta</surname><given-names>M</given-names></name><name><surname>Hatta</surname><given-names>Y</given-names></name><name><surname>Kim</surname><given-names>JH</given-names></name><etal></etal></person-group><article-title>Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice</article-title><source>PLoS Pathog</source><year>2007</year><volume>3</volume><fpage>1374</fpage><lpage>1379</lpage><pub-id pub-id-type="pmid">17922570</pub-id></element-citation></ref><ref id="B34"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Long</surname><given-names>JS</given-names></name><name><surname>Howard</surname><given-names>WA</given-names></name><name><surname>Nunez</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>The effect of the PB2 mutation 627K on highly pathogenic H5N1 avian influenza virus is dependent on the virus lineage</article-title><source>J Virol</source><year>2013</year><volume>87</volume><fpage>9983</fpage><lpage>9996</lpage><pub-id pub-id-type="pmid">23843645</pub-id></element-citation></ref><ref id="B35"><label>35</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Choi</surname><given-names>WS</given-names></name><name><surname>Baek</surname><given-names>YH</given-names></name><name><surname>Kwon</surname><given-names>JJ</given-names></name><etal></etal></person-group><article-title>Rapid acquisition of polymorphic virulence markers during adaptation of highly pathogenic avian influenza H5N8 virus in the mouse</article-title><source>Sci Rep</source><year>2017</year><volume>7</volume><fpage>40667</fpage><pub-id pub-id-type="pmid">28094780</pub-id></element-citation></ref><ref id="B36"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Han</surname><given-names>P</given-names></name><name><surname>Hu</surname><given-names>Y</given-names></name><name><surname>Sun</surname><given-names>W</given-names></name><etal></etal></person-group><article-title>Mouse lung-adapted mutation of E190G in hemagglutinin from H5N1 influenza virus contributes to attenuation in mice</article-title><source>J Med Virol</source><year>2015</year><volume>87</volume><fpage>1816</fpage><lpage>1822</lpage><pub-id pub-id-type="pmid">26089289</pub-id></element-citation></ref><ref id="B37"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smirnov</surname><given-names>YA</given-names></name><name><surname>Lipatov</surname><given-names>AS</given-names></name><name><surname>Van Beek</surname><given-names>R</given-names></name><name><surname>Gitelman</surname><given-names>AK</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>Claas</surname><given-names>EC</given-names></name></person-group><article-title>Characterization of adaptation of an avian influenza A (H5N2) virus to a mammalian host</article-title><source>Acta Virol</source><year>2000</year><volume>44</volume><fpage>1</fpage><lpage>8</lpage><pub-id pub-id-type="pmid">10989685</pub-id></element-citation></ref><ref id="B38"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>H</given-names></name><name><surname>Peng</surname><given-names>X</given-names></name><name><surname>Peng</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Multiple amino acid substitutions involved in the adaptation of avian-origin influenza A (H10N7) virus in mice</article-title><source>Arch Virol</source><year>2016</year><volume>161</volume><fpage>977</fpage><lpage>980</lpage><pub-id pub-id-type="pmid">26699787</pub-id></element-citation></ref><ref id="B39"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Taft</surname><given-names>AS</given-names></name><name><surname>Ozawa</surname><given-names>M</given-names></name><name><surname>Fitch</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Identification of mammalian-adapting mutations in the polymerase complex of an avian H5N1 influenza virus</article-title><source>Nat Commun</source><year>2015</year><volume>6</volume><fpage>7491</fpage><pub-id pub-id-type="pmid">26082035</pub-id></element-citation></ref><ref id="B40"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Vries</surname><given-names>E</given-names></name><name><surname>Guo</surname><given-names>H</given-names></name><name><surname>Dai</surname><given-names>M</given-names></name><name><surname>Rottier</surname><given-names>PJ</given-names></name><name><surname>van Kuppeveld</surname><given-names>FJ</given-names></name><name><surname>de Haan</surname><given-names>CA</given-names></name></person-group><article-title>Rapid emergence of highly pathogenic avian influenza subtypes from a subtype H5N1 hemagglutinin variant</article-title><source>Emerg Infect Dis</source><year>2015</year><volume>21</volume><fpage>842</fpage><lpage>846</lpage><pub-id pub-id-type="pmid">25897518</pub-id></element-citation></ref><ref id="B41"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dalby</surname><given-names>AR</given-names></name><name><surname>Iqbal</surname><given-names>M</given-names></name></person-group><article-title>The European and Japanese outbreaks of H5N8 derive from a single source population providing evidence for the dispersal along the long distance bird migratory flyways</article-title><source>PeerJ</source><year>2015</year><volume>3</volume><fpage>e934</fpage><pub-id pub-id-type="pmid">25945320</pub-id></element-citation></ref><ref id="B42"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saito</surname><given-names>T</given-names></name><name><surname>Tanikawa</surname><given-names>T</given-names></name><name><surname>Uchida</surname><given-names>Y</given-names></name><name><surname>Takemae</surname><given-names>N</given-names></name><name><surname>Kanehira</surname><given-names>K</given-names></name><name><surname>Tsunekuni</surname><given-names>R</given-names></name></person-group><article-title>Intracontinental and intercontinental dissemination of Asian H5 highly pathogenic avian influenza virus (clade 2.3.4.4) in the winter of 2014-2015</article-title><source>Rev Med Virol</source><year>2015</year><volume>25</volume><fpage>388</fpage><lpage>405</lpage><pub-id pub-id-type="pmid">26458727</pub-id></element-citation></ref><ref id="B43"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gu</surname><given-names>M</given-names></name><name><surname>Liu</surname><given-names>W</given-names></name><name><surname>Cao</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Novel reassortant highly pathogenic avian influenza (H5N5) viruses in domestic ducks, China</article-title><source>Emerg Infect Dis</source><year>2011</year><volume>17</volume><fpage>1060</fpage><lpage>1063</lpage><pub-id pub-id-type="pmid">21749770</pub-id></element-citation></ref><ref id="B44"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berhane</surname><given-names>Y</given-names></name><name><surname>Kobasa</surname><given-names>D</given-names></name><name><surname>Embury-Hyatt</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Pathobiological characterization of a novel reassortant highly pathogenic H5N1 virus isolated in British Columbia, Canada, 2015</article-title><source>Sci Rep</source><year>2016</year><volume>6</volume><fpage>23380</fpage><pub-id pub-id-type="pmid">26988892</pub-id></element-citation></ref><ref id="B45"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>YI</given-names></name><name><surname>Pascua</surname><given-names>PN</given-names></name><name><surname>Kwon</surname><given-names>HI</given-names></name><etal></etal></person-group><article-title>Pathobiological features of a novel, highly pathogenic avian influenza A(H5N8) virus</article-title><source>Emerg Microbes Infect</source><year>2014</year><volume>3</volume><fpage>e75</fpage><pub-id pub-id-type="pmid">26038499</pub-id></element-citation></ref><ref id="B46"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pulit-Penaloza</surname><given-names>JA</given-names></name><name><surname>Sun</surname><given-names>X</given-names></name><name><surname>Creager</surname><given-names>HM</given-names></name><etal></etal></person-group><article-title>Pathogenesis and transmission of novel highly pathogenic avian influenza H5N2 and H5N8 viruses in ferrets and mice</article-title><source>J Virol</source><year>2015</year><volume>89</volume><fpage>10286</fpage><lpage>10293</lpage><pub-id pub-id-type="pmid">26223637</pub-id></element-citation></ref><ref id="B47"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>Q</given-names></name><name><surname>Wang</surname><given-names>X</given-names></name><name><surname>Zhong</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Adaptation of a natural reassortant H5N2 avian influenza virus in mice</article-title><source>Vet Microbiol</source><year>2014</year><volume>172</volume><fpage>568</fpage><lpage>574</lpage><pub-id pub-id-type="pmid">25037995</pub-id></element-citation></ref><ref id="B48"><label>48</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Peng</surname><given-names>X</given-names></name><name><surname>Wu</surname><given-names>H</given-names></name><name><surname>Peng</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Amino acid substitutions occurring during adaptation of an emergent H5N6 avian influenza virus to mammals</article-title><source>Arch Virol</source><year>2016</year><volume>161</volume><fpage>1665</fpage><lpage>1670</lpage><pub-id pub-id-type="pmid">26997612</pub-id></element-citation></ref><ref id="B49"><label>49</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>H</given-names></name><name><surname>Peng</surname><given-names>X</given-names></name><name><surname>Peng</surname><given-names>X</given-names></name><name><surname>Wu</surname><given-names>N</given-names></name></person-group><article-title>Amino acid substitutions involved in the adaptation of a novel highly pathogenic H5N2 avian influenza virus in mice</article-title><source>Virol J</source><year>2016</year><volume>13</volume><fpage>159</fpage><pub-id pub-id-type="pmid">27663652</pub-id></element-citation></ref><ref id="B50"><label>50</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Capua</surname><given-names>I</given-names></name><name><surname>Mutinelli</surname><given-names>F</given-names></name><name><surname>Bozza</surname><given-names>MA</given-names></name><name><surname>Terregino</surname><given-names>C</given-names></name><name><surname>Cattoli</surname><given-names>G</given-names></name></person-group><article-title>Highly pathogenic avian influenza (H7N1) in ostriches (Struthio camelus)</article-title><source>Avian Pathol</source><year>2000</year><volume>29</volume><fpage>643</fpage><lpage>646</lpage><pub-id pub-id-type="pmid">19184863</pub-id></element-citation></ref><ref id="B51"><label>51</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pasick</surname><given-names>J</given-names></name><name><surname>Berhane</surname><given-names>Y</given-names></name><name><surname>Hisanaga</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Diagnostic test results and pathology associated with the 2007 Canadian H7N3 highly pathogenic avian influenza outbreak</article-title><source>Avian Dis</source><year>2010</year><volume>54</volume><issue>1 Suppl</issue><fpage>213</fpage><lpage>219</lpage><pub-id pub-id-type="pmid">20521634</pub-id></element-citation></ref><ref id="B52"><label>52</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>van den Berg</surname><given-names>T</given-names></name><name><surname>Houdart</surname><given-names>P</given-names></name></person-group><article-title>Avian influenza outbreak management: action at time of confirmation, depopulation and disposal methods; the ‘Belgian experience’ during the H7N7 highly pathogenic avian influenza epidemic in 2003</article-title><source>Zoonoses Public Health</source><year>2008</year><volume>55</volume><fpage>54</fpage><lpage>64</lpage><pub-id pub-id-type="pmid">18201328</pub-id></element-citation></ref><ref id="B53"><label>53</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zanin</surname><given-names>M</given-names></name><name><surname>Kocer</surname><given-names>ZA</given-names></name><name><surname>Poulson</surname><given-names>RL</given-names></name><etal></etal></person-group><article-title>Potential for low-pathogenic avian H7 influenza A viruses to replicate and cause disease in a mammalian model</article-title><source>J Virol</source><year>2017</year><volume>91</volume><fpage>e01934</fpage><lpage>e01916</lpage><pub-id pub-id-type="pmid">27852855</pub-id></element-citation></ref><ref id="B54"><label>54</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>YI</given-names></name><name><surname>Kim</surname><given-names>SW</given-names></name><name><surname>Si</surname><given-names>YJ</given-names></name><etal></etal></person-group><article-title>Genetic diversity and pathogenic potential of low pathogenic H7 avian influenza viruses isolated from wild migratory birds in Korea</article-title><source>Infect Genet Evol</source><year>2016</year><volume>45</volume><fpage>268</fpage><lpage>284</lpage><pub-id pub-id-type="pmid">27615552</pub-id></element-citation></ref><ref id="B55"><label>55</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Joseph</surname><given-names>T</given-names></name><name><surname>McAuliffe</surname><given-names>J</given-names></name><name><surname>Lu</surname><given-names>B</given-names></name><name><surname>Jin</surname><given-names>H</given-names></name><name><surname>Kemble</surname><given-names>G</given-names></name><name><surname>Subbarao</surname><given-names>K</given-names></name></person-group><article-title>Evaluation of replication and pathogenicity of avian influenza a H7 subtype viruses in a mouse model</article-title><source>J Virol</source><year>2007</year><volume>81</volume><fpage>10558</fpage><lpage>10566</lpage><pub-id pub-id-type="pmid">17634234</pub-id></element-citation></ref><ref id="B56"><label>56</label><element-citation publication-type="book"><collab>Food Agriculture Organization</collab><source>Diseases Events (search criteria: disease list; H5N1 HPAI, H5N6 HPAI, H7N9 LPAI, H7N9 HPAI/animal affected; human) [Internet]</source><publisher-loc>Rome</publisher-loc><publisher-name>Food Agriculture Organization</publisher-name><year>2017</year><date-in-citation content-type="access-date">cited 2017 May 1</date-in-citation><comment>Available from: <ext-link ext-link-type="uri" xlink:href="http://empres-i.fao.org/eipws3g/">http://empres-i.fao.org/eipws3g/</ext-link></comment></element-citation></ref><ref id="B57"><label>57</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Jong</surname><given-names>RM</given-names></name><name><surname>Stockhofe-Zurwieden</surname><given-names>N</given-names></name><name><surname>Verheij</surname><given-names>ES</given-names></name><etal></etal></person-group><article-title>Rapid emergence of a virulent PB2 E627K variant during adaptation of highly pathogenic avian influenza H7N7 virus to mice</article-title><source>Virol J</source><year>2013</year><volume>10</volume><fpage>276</fpage><pub-id pub-id-type="pmid">24007444</pub-id></element-citation></ref><ref id="B58"><label>58</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gabriel</surname><given-names>G</given-names></name><name><surname>Dauber</surname><given-names>B</given-names></name><name><surname>Wolff</surname><given-names>T</given-names></name><name><surname>Planz</surname><given-names>O</given-names></name><name><surname>Klenk</surname><given-names>HD</given-names></name><name><surname>Stech</surname><given-names>J</given-names></name></person-group><article-title>The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host</article-title><source>Proc Natl Acad Sci U S A</source><year>2005</year><volume>102</volume><fpage>18590</fpage><lpage>18595</lpage><pub-id pub-id-type="pmid">16339318</pub-id></element-citation></ref><ref id="B59"><label>59</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yu</surname><given-names>Z</given-names></name><name><surname>Sun</surname><given-names>W</given-names></name><name><surname>Li</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Adaptive amino acid substitutions enhance the virulence of a reassortant H7N1 avian influenza virus isolated from wild waterfowl in mice</article-title><source>Virology</source><year>2015</year><volume>476</volume><fpage>233</fpage><lpage>239</lpage><pub-id pub-id-type="pmid">25555151</pub-id></element-citation></ref><ref id="B60"><label>60</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>Q</given-names></name><name><surname>Yu</surname><given-names>Z</given-names></name><name><surname>Sun</surname><given-names>W</given-names></name><etal></etal></person-group><article-title>Adaptive amino acid substitutions enhance the virulence of an H7N7 avian influenza virus isolated from wild waterfowl in mice</article-title><source>Vet Microbiol</source><year>2015</year><volume>177</volume><fpage>18</fpage><lpage>24</lpage><pub-id pub-id-type="pmid">25769645</pub-id></element-citation></ref><ref id="B61"><label>61</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>Y</given-names></name><name><surname>Yu</surname><given-names>Z</given-names></name><name><surname>Liu</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Adaptive amino acid substitutions enhance the virulence of a novel human H7N9 influenza virus in mice</article-title><source>Vet Microbiol</source><year>2016</year><volume>187</volume><fpage>8</fpage><lpage>14</lpage><pub-id pub-id-type="pmid">27066703</pub-id></element-citation></ref><ref id="B62"><label>62</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shinya</surname><given-names>K</given-names></name><name><surname>Watanabe</surname><given-names>S</given-names></name><name><surname>Ito</surname><given-names>T</given-names></name><name><surname>Kasai</surname><given-names>N</given-names></name><name><surname>Kawaoka</surname><given-names>Y</given-names></name></person-group><article-title>Adaptation of an H7N7 equine influenza A virus in mice</article-title><source>J Gen Virol</source><year>2007</year><volume>88</volume><issue>Pt 2</issue><fpage>547</fpage><lpage>553</lpage><pub-id pub-id-type="pmid">17251573</pub-id></element-citation></ref><ref id="B63"><label>63</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brown</surname><given-names>EG</given-names></name><name><surname>Liu</surname><given-names>H</given-names></name><name><surname>Kit</surname><given-names>LC</given-names></name><name><surname>Baird</surname><given-names>S</given-names></name><name><surname>Nesrallah</surname><given-names>M</given-names></name></person-group><article-title>Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: identification of functional themes</article-title><source>Proc Natl Acad Sci U S A</source><year>2001</year><volume>98</volume><fpage>6883</fpage><lpage>6888</lpage><pub-id pub-id-type="pmid">11371620</pub-id></element-citation></ref><ref id="B64"><label>64</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Homme</surname><given-names>PJ</given-names></name><name><surname>Easterday</surname><given-names>BC</given-names></name></person-group><article-title>Avian influenza virus infections. I. Characteristics of influenza A-turkey-Wisconsin-1966 virus</article-title><source>Avian Dis</source><year>1970</year><volume>14</volume><fpage>66</fpage><lpage>74</lpage><pub-id pub-id-type="pmid">4314007</pub-id></element-citation></ref><ref id="B65"><label>65</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guo</surname><given-names>YJ</given-names></name><name><surname>Krauss</surname><given-names>S</given-names></name><name><surname>Senne</surname><given-names>DA</given-names></name><etal></etal></person-group><article-title>Characterization of the pathogenicity of members of the newly established H9N2 influenza virus lineages in Asia</article-title><source>Virology</source><year>2000</year><volume>267</volume><fpage>279</fpage><lpage>288</lpage><pub-id pub-id-type="pmid">10662623</pub-id></element-citation></ref><ref id="B66"><label>66</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Peiris</surname><given-names>M</given-names></name><name><surname>Yuen</surname><given-names>KY</given-names></name><name><surname>Leung</surname><given-names>CW</given-names></name><etal></etal></person-group><article-title>Human infection with influenza H9N2</article-title><source>Lancet</source><year>1999</year><volume>354</volume><fpage>916</fpage><lpage>917</lpage><pub-id pub-id-type="pmid">10489954</pub-id></element-citation></ref><ref id="B67"><label>67</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Khan</surname><given-names>SU</given-names></name><name><surname>Anderson</surname><given-names>BD</given-names></name><name><surname>Heil</surname><given-names>GL</given-names></name><name><surname>Liang</surname><given-names>S</given-names></name><name><surname>Gray</surname><given-names>GC</given-names></name></person-group><article-title>A systematic review and meta-analysis of the seroprevalence of influenza A(H9N2) infection among humans</article-title><source>J Infect Dis</source><year>2015</year><volume>212</volume><fpage>562</fpage><lpage>569</lpage><pub-id pub-id-type="pmid">25712969</pub-id></element-citation></ref><ref id="B68"><label>68</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guan</surname><given-names>Y</given-names></name><name><surname>Shortridge</surname><given-names>KF</given-names></name><name><surname>Krauss</surname><given-names>S</given-names></name><name><surname>Webster</surname><given-names>RG</given-names></name></person-group><article-title>Molecular characterization of H9N2 influenza viruses: were they the donors of the “internal” genes of H5N1 viruses in Hong Kong?</article-title><source>Proc Natl Acad Sci U S A</source><year>1999</year><volume>96</volume><fpage>9363</fpage><lpage>9367</lpage><pub-id pub-id-type="pmid">10430948</pub-id></element-citation></ref><ref id="B69"><label>69</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname><given-names>L</given-names></name><name><surname>Zhu</surname><given-names>W</given-names></name><name><surname>Li</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Genesis and dissemination of highly pathogenic H5N6 avian influenza viruses</article-title><source>J Virol</source><year>2017</year><volume>91</volume><fpage>e02199</fpage><lpage>e02116</lpage><pub-id pub-id-type="pmid">28003485</pub-id></element-citation></ref><ref id="B70"><label>70</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>A</given-names></name><name><surname>Su</surname><given-names>C</given-names></name><name><surname>Wang</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Sequential reassortments underlie diverse influenza H7N9 genotypes in China</article-title><source>Cell Host Microbe</source><year>2013</year><volume>14</volume><fpage>446</fpage><lpage>452</lpage><pub-id pub-id-type="pmid">24055604</pub-id></element-citation></ref><ref id="B71"><label>71</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>D</given-names></name><name><surname>Shi</surname><given-names>W</given-names></name><name><surname>Gao</surname><given-names>GF</given-names></name></person-group><article-title>Poultry carrying H9N2 act as incubators for novel human avian influenza viruses</article-title><source>Lancet</source><year>2014</year><volume>383</volume><fpage>869</fpage><pub-id pub-id-type="pmid">24581684</pub-id></element-citation></ref><ref id="B72"><label>72</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>YJ</given-names></name><name><surname>Shin</surname><given-names>JY</given-names></name><name><surname>Song</surname><given-names>MS</given-names></name><etal></etal></person-group><article-title>Continuing evolution of H9 influenza viruses in Korean poultry</article-title><source>Virology</source><year>2007</year><volume>359</volume><fpage>313</fpage><lpage>323</lpage><pub-id pub-id-type="pmid">17056087</pub-id></element-citation></ref><ref id="B73"><label>73</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Choi</surname><given-names>YK</given-names></name><name><surname>Seo</surname><given-names>SH</given-names></name><name><surname>Kim</surname><given-names>JA</given-names></name><name><surname>Webby</surname><given-names>RJ</given-names></name><name><surname>Webster</surname><given-names>RG</given-names></name></person-group><article-title>Avian influenza viruses in Korean live poultry markets and their pathogenic potential</article-title><source>Virology</source><year>2005</year><volume>332</volume><fpage>529</fpage><lpage>537</lpage><pub-id pub-id-type="pmid">15680418</pub-id></element-citation></ref><ref id="B74"><label>74</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>H</given-names></name><name><surname>Xu</surname><given-names>B</given-names></name><name><surname>Chen</surname><given-names>Q</given-names></name><name><surname>Chen</surname><given-names>Z</given-names></name></person-group><article-title>Characterization of H9N2 influenza viruses isolated from Dongting Lake wetland in 2007</article-title><source>Arch Virol</source><year>2011</year><volume>156</volume><fpage>95</fpage><lpage>105</lpage><pub-id pub-id-type="pmid">21053033</pub-id></element-citation></ref><ref id="B75"><label>75</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>R</given-names></name><name><surname>Zhang</surname><given-names>H</given-names></name><name><surname>Yang</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>Multiple amino acid substitutions are involved in the adaptation of H9N2 avian influenza virus to mice</article-title><source>Vet Microbiol</source><year>2009</year><volume>138</volume><fpage>85</fpage><lpage>91</lpage><pub-id pub-id-type="pmid">19342184</pub-id></element-citation></ref><ref id="B76"><label>76</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>Z</given-names></name><name><surname>Hu</surname><given-names>S</given-names></name><name><surname>Li</surname><given-names>Z</given-names></name><etal></etal></person-group><article-title>Multiple amino acid substitutions involved in enhanced pathogenicity of LPAI H9N2 in mice</article-title><source>Infect Genet Evol</source><year>2011</year><volume>11</volume><fpage>1790</fpage><lpage>1797</lpage><pub-id pub-id-type="pmid">21896338</pub-id></element-citation></ref><ref id="B77"><label>77</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>J</given-names></name><name><surname>Sun</surname><given-names>Y</given-names></name><name><surname>Xu</surname><given-names>Q</given-names></name><etal></etal></person-group><article-title>Mouse-adapted H9N2 influenza A virus PB2 protein M147L and E627K mutations are critical for high virulence</article-title><source>PLoS One</source><year>2012</year><volume>7</volume><fpage>e40752</fpage><pub-id pub-id-type="pmid">22808250</pub-id></element-citation></ref><ref id="B78"><label>78</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>Q</given-names></name><name><surname>Huang</surname><given-names>J</given-names></name><name><surname>Chen</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Virulence determinants in the PB2 gene of a mouse-adapted H9N2 virus</article-title><source>J Virol</source><year>2015</year><volume>89</volume><fpage>877</fpage><lpage>882</lpage><pub-id pub-id-type="pmid">25339773</pub-id></element-citation></ref><ref id="B79"><label>79</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>Q</given-names></name><name><surname>Chen</surname><given-names>H</given-names></name><name><surname>Huang</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>A nonpathogenic duck-origin H9N2 influenza A virus adapts to high pathogenicity in mice</article-title><source>Arch Virol</source><year>2014</year><volume>159</volume><fpage>2243</fpage><lpage>2252</lpage><pub-id pub-id-type="pmid">24696271</pub-id></element-citation></ref><ref id="B80"><label>80</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sang</surname><given-names>X</given-names></name><name><surname>Wang</surname><given-names>A</given-names></name><name><surname>Chai</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Rapid emergence of a PB2-E627K substitution confers a virulent phenotype to an H9N2 avian influenza virus during adoption in mice</article-title><source>Arch Virol</source><year>2015</year><volume>160</volume><fpage>1267</fpage><lpage>1277</lpage><pub-id pub-id-type="pmid">25782865</pub-id></element-citation></ref><ref id="B81"><label>81</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Park</surname><given-names>KJ</given-names></name><name><surname>Song</surname><given-names>MS</given-names></name><name><surname>Kim</surname><given-names>EH</given-names></name><etal></etal></person-group><article-title>Molecular characterization of mammalian-adapted Korean-type avian H9N2 virus and evaluation of its virulence in mice</article-title><source>J Microbiol</source><year>2015</year><volume>53</volume><fpage>570</fpage><lpage>577</lpage><pub-id pub-id-type="pmid">26224460</pub-id></element-citation></ref><ref id="B82"><label>82</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>Q</given-names></name><name><surname>Wang</surname><given-names>X</given-names></name><name><surname>Sun</surname><given-names>Z</given-names></name><etal></etal></person-group><article-title>Adaptive mutations in PB2 gene contribute to the high virulence of a natural reassortant H5N2 avian influenza virus in mice</article-title><source>Virus Res</source><year>2015</year><volume>210</volume><fpage>255</fpage><lpage>263</lpage><pub-id pub-id-type="pmid">26315686</pub-id></element-citation></ref><ref id="B83"><label>83</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yu</surname><given-names>Z</given-names></name><name><surname>Cheng</surname><given-names>K</given-names></name><name><surname>Xin</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Multiple amino acid substitutions involved in the adaptation of H6N1 avian influenza virus in mice</article-title><source>Vet Microbiol</source><year>2014</year><volume>174</volume><fpage>316</fpage><lpage>321</lpage><pub-id pub-id-type="pmid">25457364</pub-id></element-citation></ref><ref id="B84"><label>84</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tan</surname><given-names>L</given-names></name><name><surname>Su</surname><given-names>S</given-names></name><name><surname>Smith</surname><given-names>DK</given-names></name><etal></etal></person-group><article-title>A combination of HA and PA mutations enhances virulence in a mouse-adapted H6N6 influenza A virus</article-title><source>J Virol</source><year>2014</year><volume>88</volume><fpage>14116</fpage><lpage>14125</lpage><pub-id pub-id-type="pmid">25275121</pub-id></element-citation></ref><ref id="B85"><label>85</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yao</surname><given-names>Y</given-names></name><name><surname>Wang</surname><given-names>H</given-names></name><name><surname>Chen</surname><given-names>Q</given-names></name><etal></etal></person-group><article-title>Characterization of low-pathogenic H6N6 avian influenza viruses in central China</article-title><source>Arch Virol</source><year>2013</year><volume>158</volume><fpage>367</fpage><lpage>377</lpage><pub-id pub-id-type="pmid">23053524</pub-id></element-citation></ref><ref id="B86"><label>86</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mei</surname><given-names>K</given-names></name><name><surname>Liu</surname><given-names>G</given-names></name><name><surname>Chen</surname><given-names>Z</given-names></name><etal></etal></person-group><article-title>Deep sequencing reveals the viral adaptation process of environment-derived H10N8 in mice</article-title><source>Infect Genet Evol</source><year>2016</year><volume>37</volume><fpage>8</fpage><lpage>13</lpage><pub-id pub-id-type="pmid">26477933</pub-id></element-citation></ref><ref id="B87"><label>87</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tian</surname><given-names>J</given-names></name><name><surname>Qi</surname><given-names>W</given-names></name><name><surname>Li</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>A single E627K mutation in the PB2 protein of H9N2 avian influenza virus increases virulence by inducing higher glucocorticoids (GCs) level</article-title><source>PLoS One</source><year>2012</year><volume>7</volume><fpage>e38233</fpage><pub-id pub-id-type="pmid">22719870</pub-id></element-citation></ref><ref id="B88"><label>88</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Su</surname><given-names>S</given-names></name><name><surname>Bi</surname><given-names>Y</given-names></name><name><surname>Wong</surname><given-names>G</given-names></name><name><surname>Gray</surname><given-names>GC</given-names></name><name><surname>Gao</surname><given-names>GF</given-names></name><name><surname>Li</surname><given-names>S</given-names></name></person-group><article-title>Epidemiology, evolution, and recent outbreaks of avian influenza virus in China</article-title><source>J Virol</source><year>2015</year><volume>89</volume><fpage>8671</fpage><lpage>8676</lpage><pub-id pub-id-type="pmid">26063419</pub-id></element-citation></ref><ref id="B89"><label>89</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>M</given-names></name><name><surname>Li</surname><given-names>X</given-names></name><name><surname>Yuan</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Genetic diversity of avian influenza A (H10N8) virus in live poultry markets and its association with human infections in China</article-title><source>Sci Rep</source><year>2015</year><volume>5</volume><fpage>7632</fpage><pub-id pub-id-type="pmid">25591167</pub-id></element-citation></ref><ref id="B90"><label>90</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shi</surname><given-names>W</given-names></name><name><surname>Shi</surname><given-names>Y</given-names></name><name><surname>Wu</surname><given-names>Y</given-names></name><name><surname>Liu</surname><given-names>D</given-names></name><name><surname>Gao</surname><given-names>GF</given-names></name></person-group><article-title>Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan</article-title><source>Protein Cell</source><year>2013</year><volume>4</volume><fpage>846</fpage><lpage>853</lpage><pub-id pub-id-type="pmid">24136722</pub-id></element-citation></ref><ref id="B91"><label>91</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tzarum</surname><given-names>N</given-names></name><name><surname>de Vries</surname><given-names>RP</given-names></name><name><surname>Zhu</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Structure and receptor binding of the hemagglutinin from a human H6N1 influenza virus</article-title><source>Cell Host Microbe</source><year>2015</year><volume>17</volume><fpage>369</fpage><lpage>376</lpage><pub-id pub-id-type="pmid">25766295</pub-id></element-citation></ref><ref id="B92"><label>92</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>G</given-names></name><name><surname>Deng</surname><given-names>G</given-names></name><name><surname>Shi</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>H6 influenza viruses pose a potential threat to human health</article-title><source>J Virol</source><year>2014</year><volume>88</volume><fpage>3953</fpage><lpage>3964</lpage><pub-id pub-id-type="pmid">24501418</pub-id></element-citation></ref><ref id="B93"><label>93</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nam</surname><given-names>JH</given-names></name><name><surname>Kim</surname><given-names>EH</given-names></name><name><surname>Song</surname><given-names>D</given-names></name><name><surname>Choi</surname><given-names>YK</given-names></name><name><surname>Kim</surname><given-names>JK</given-names></name><name><surname>Poo</surname><given-names>H</given-names></name></person-group><article-title>Emergence of mammalian species-infectious and -pathogenic avian influenza H6N5 virus with no evidence of adaptation</article-title><source>J Virol</source><year>2011</year><volume>85</volume><fpage>13271</fpage><lpage>13277</lpage><pub-id pub-id-type="pmid">21994462</pub-id></element-citation></ref><ref id="B94"><label>94</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gillim-Ross</surname><given-names>L</given-names></name><name><surname>Santos</surname><given-names>C</given-names></name><name><surname>Chen</surname><given-names>Z</given-names></name><etal></etal></person-group><article-title>Avian influenza h6 viruses productively infect and cause illness in mice and ferrets</article-title><source>J Virol</source><year>2008</year><volume>82</volume><fpage>10854</fpage><lpage>10863</lpage><pub-id pub-id-type="pmid">18715930</pub-id></element-citation></ref><ref id="B95"><label>95</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>HR</given-names></name><name><surname>Lee</surname><given-names>YJ</given-names></name><name><surname>Lee</surname><given-names>KK</given-names></name><etal></etal></person-group><article-title>Genetic relatedness of H6 subtype avian influenza viruses isolated from wild birds and domestic ducks in Korea and their pathogenicity in animals</article-title><source>J Gen Virol</source><year>2010</year><volume>91</volume><issue>Pt 1</issue><fpage>208</fpage><lpage>219</lpage><pub-id pub-id-type="pmid">19812266</pub-id></element-citation></ref><ref id="B96"><label>96</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>H</given-names></name><name><surname>Lu</surname><given-names>R</given-names></name><name><surname>Wu</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Isolation and characterization of a novel H10N2 avian influenza virus from a domestic duck in Eastern China</article-title><source>Infect Genet Evol</source><year>2015</year><volume>29</volume><fpage>1</fpage><lpage>5</lpage><pub-id pub-id-type="pmid">25445651</pub-id></element-citation></ref><ref id="B97"><label>97</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>H</given-names></name><name><surname>Lu</surname><given-names>R</given-names></name><name><surname>Wu</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Novel reassortant H10N7 avian influenza viruses isolated from chickens in Eastern China</article-title><source>J Clin Virol</source><year>2015</year><volume>65</volume><fpage>58</fpage><lpage>61</lpage><pub-id pub-id-type="pmid">25766990</pub-id></element-citation></ref><ref id="B98"><label>98</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>M</given-names></name><name><surname>Zhang</surname><given-names>X</given-names></name><name><surname>Xu</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>Characterization of the pathogenesis of H10N3, H10N7, and H10N8 subtype avian influenza viruses circulating in ducks</article-title><source>Sci Rep</source><year>2016</year><volume>6</volume><fpage>34489</fpage><pub-id pub-id-type="pmid">27678170</pub-id></element-citation></ref><ref id="B99"><label>99</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>H</given-names></name><name><surname>Huang</surname><given-names>L</given-names></name><name><surname>Li</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>High pathogenicity of influenza A (H10N8) virus in mice</article-title><source>Am J Trop Med Hyg</source><year>2015</year><volume>93</volume><fpage>1360</fpage><lpage>1363</lpage><pub-id pub-id-type="pmid">26350451</pub-id></element-citation></ref><ref id="B100"><label>100</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Francis</surname><given-names>T</given-names></name><name><surname>Magill</surname><given-names>TP</given-names></name></person-group><article-title>Immunological studies with the virus of influenza</article-title><source>J Exp Med</source><year>1935</year><volume>62</volume><fpage>505</fpage><lpage>516</lpage><pub-id pub-id-type="pmid">19870430</pub-id></element-citation></ref><ref id="B101"><label>101</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>YT</given-names></name><name><surname>Kim</surname><given-names>KH</given-names></name><name><surname>Ko</surname><given-names>EJ</given-names></name><etal></etal></person-group><article-title>New vaccines against influenza virus</article-title><source>Clin Exp Vaccine Res</source><year>2014</year><volume>3</volume><fpage>12</fpage><lpage>28</lpage><pub-id pub-id-type="pmid">24427759</pub-id></element-citation></ref><ref id="B102"><label>102</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jang</surname><given-names>YH</given-names></name><name><surname>Byun</surname><given-names>YH</given-names></name><name><surname>Lee</surname><given-names>YJ</given-names></name><name><surname>Lee</surname><given-names>YH</given-names></name><name><surname>Lee</surname><given-names>KH</given-names></name><name><surname>Seong</surname><given-names>BL</given-names></name></person-group><article-title>Cold-adapted pandemic 2009 H1N1 influenza virus live vaccine elicits cross-reactive immune responses against seasonal and H5 influenza A viruses</article-title><source>J Virol</source><year>2012</year><volume>86</volume><fpage>5953</fpage><lpage>5958</lpage><pub-id pub-id-type="pmid">22438541</pub-id></element-citation></ref><ref id="B103"><label>103</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>SM</given-names></name><name><surname>Kim</surname><given-names>YI</given-names></name><name><surname>Park</surname><given-names>SJ</given-names></name><etal></etal></person-group><article-title>Vaccine efficacy of inactivated, chimeric hemagglutinin H9/H5N2 avian influenza virus and its suitability for the marker vaccine strategy</article-title><source>J Virol</source><year>2017</year><volume>91</volume><fpage>e01693</fpage><lpage>e01616</lpage><pub-id pub-id-type="pmid">28077631</pub-id></element-citation></ref><ref id="B104"><label>104</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Choi</surname><given-names>EH</given-names></name><name><surname>Song</surname><given-names>MS</given-names></name><name><surname>Park</surname><given-names>SJ</given-names></name><etal></etal></person-group><article-title>Development of a dual-protective live attenuated vaccine against H5N1 and H9N2 avian influenza viruses by modifying the NS1 gene</article-title><source>Arch Virol</source><year>2015</year><volume>160</volume><fpage>1729</fpage><lpage>1740</lpage><pub-id pub-id-type="pmid">25959557</pub-id></element-citation></ref><ref id="B105"><label>105</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Song</surname><given-names>MS</given-names></name><name><surname>Moon</surname><given-names>HJ</given-names></name><name><surname>Kwon</surname><given-names>HI</given-names></name><etal></etal></person-group><article-title>Evaluation of the efficacy of a pre-pandemic H5N1 vaccine (MG1109) in mouse and ferret models</article-title><source>J Microbiol</source><year>2012</year><volume>50</volume><fpage>478</fpage><lpage>488</lpage><pub-id pub-id-type="pmid">22752912</pub-id></element-citation></ref><ref id="B106"><label>106</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shim</surname><given-names>BS</given-names></name><name><surname>Choi</surname><given-names>YK</given-names></name><name><surname>Yun</surname><given-names>CH</given-names></name><etal></etal></person-group><article-title>Sublingual immunization with M2-based vaccine induces broad protective immunity against influenza</article-title><source>PLoS One</source><year>2011</year><volume>6</volume><fpage>e27953</fpage><pub-id pub-id-type="pmid">22140491</pub-id></element-citation></ref><ref id="B107"><label>107</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Park</surname><given-names>KS</given-names></name><name><surname>Lee</surname><given-names>J</given-names></name><name><surname>Ahn</surname><given-names>SS</given-names></name><etal></etal></person-group><article-title>Mucosal immunity induced by adenovirus-based H5N1 HPAI vaccine confers protection against a lethal H5N2 avian influenza virus challenge</article-title><source>Virology</source><year>2009</year><volume>395</volume><fpage>182</fpage><lpage>189</lpage><pub-id pub-id-type="pmid">19836045</pub-id></element-citation></ref><ref id="B108"><label>108</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Park</surname><given-names>KS</given-names></name><name><surname>Seo</surname><given-names>YB</given-names></name><name><surname>Lee</surname><given-names>JY</given-names></name><etal></etal></person-group><article-title>Complete protection against a H5N2 avian influenza virus by a DNA vaccine expressing a fusion protein of H1N1 HA and M2e</article-title><source>Vaccine</source><year>2011</year><volume>29</volume><fpage>5481</fpage><lpage>5487</lpage><pub-id pub-id-type="pmid">21664216</pub-id></element-citation></ref><ref id="B109"><label>109</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>EH</given-names></name><name><surname>Lee</surname><given-names>JH</given-names></name><name><surname>Pascua</surname><given-names>PN</given-names></name><etal></etal></person-group><article-title>Prokaryote-expressed M2e protein improves H9N2 influenza vaccine efficacy and protection against lethal influenza A virus in mice</article-title><source>Virol J</source><year>2013</year><volume>10</volume><fpage>104</fpage><pub-id pub-id-type="pmid">23551908</pub-id></element-citation></ref><ref id="B110"><label>110</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takahashi</surname><given-names>K</given-names></name><name><surname>Moyo</surname><given-names>P</given-names></name><name><surname>Chigweshe</surname><given-names>L</given-names></name><name><surname>Chang</surname><given-names>WC</given-names></name><name><surname>White</surname><given-names>MR</given-names></name><name><surname>Hartshorn</surname><given-names>KL</given-names></name></person-group><article-title>Efficacy of recombinant chimeric lectins, consisting of mannose binding lectin and L-ficolin, against influenza A viral infection in mouse model study</article-title><source>Virus Res</source><year>2013</year><volume>178</volume><fpage>495</fpage><lpage>501</lpage><pub-id pub-id-type="pmid">24140629</pub-id></element-citation></ref><ref id="B111"><label>111</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>D'Agostini</surname><given-names>C</given-names></name><name><surname>Palamara</surname><given-names>AT</given-names></name><name><surname>Favalli</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Efficacy of combination therapy with amantadine, thymosin alpha 1 and alpha/beta interferon in mice infected with influenza A virus</article-title><source>Int J Immunopharmacol</source><year>1996</year><volume>18</volume><fpage>95</fpage><lpage>102</lpage><pub-id pub-id-type="pmid">8799359</pub-id></element-citation></ref><ref id="B112"><label>112</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sidwell</surname><given-names>RW</given-names></name><name><surname>Huffman</surname><given-names>JH</given-names></name><name><surname>Barnard</surname><given-names>DL</given-names></name><etal></etal></person-group><article-title>Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor</article-title><source>Antiviral Res</source><year>1998</year><volume>37</volume><fpage>107</fpage><lpage>120</lpage><pub-id pub-id-type="pmid">9588843</pub-id></element-citation></ref><ref id="B113"><label>113</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Govorkova</surname><given-names>EA</given-names></name><name><surname>Leneva</surname><given-names>IA</given-names></name><name><surname>Goloubeva</surname><given-names>OG</given-names></name><name><surname>Bush</surname><given-names>K</given-names></name><name><surname>Webster</surname><given-names>RG</given-names></name></person-group><article-title>Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses</article-title><source>Antimicrob Agents Chemother</source><year>2001</year><volume>45</volume><fpage>2723</fpage><lpage>2732</lpage><pub-id pub-id-type="pmid">11557461</pub-id></element-citation></ref><ref id="B114"><label>114</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lipatov</surname><given-names>AS</given-names></name><name><surname>Gitelman</surname><given-names>AK</given-names></name><name><surname>Smirnov</surname><given-names>YA</given-names></name></person-group><article-title>Differences between original strains and their mouse-adapted variants of human (H1) and avian (H2) influenza A viruses in the reaction with cross-neutralizing monoclonal antibody recognizing conformational epitope</article-title><source>Acta Virol</source><year>1996</year><volume>40</volume><fpage>227</fpage><lpage>230</lpage><pub-id pub-id-type="pmid">9014015</pub-id></element-citation></ref><ref id="B115"><label>115</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gitelman</surname><given-names>AK</given-names></name><name><surname>Kaverin</surname><given-names>NV</given-names></name><name><surname>Kharitonenkov</surname><given-names>IG</given-names></name><name><surname>Rudneva</surname><given-names>IA</given-names></name><name><surname>Zhdanov</surname><given-names>VM</given-names></name></person-group><article-title>Changes in the antigenic specificity of influenza hemagglutinin in the course of adaptation to mice</article-title><source>Virology</source><year>1984</year><volume>134</volume><fpage>230</fpage><lpage>232</lpage><pub-id pub-id-type="pmid">6200993</pub-id></element-citation></ref><ref id="B116"><label>116</label><element-citation publication-type="book"><collab>World Health Oranization</collab><source>Cumulative number of confirmed human cases of avian influenza A(H5N1) reported to WHO [Internet]</source><publisher-loc>Geneva</publisher-loc><publisher-name>World Health Organization</publisher-name><date-in-citation content-type="access-date">cited 2017 May 1</date-in-citation><comment>Available from: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/">http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/</ext-link></comment></element-citation></ref></ref-list></back><floats-group><table-wrap id="T1" orientation="portrait" position="float"><label>Table 1</label><caption><title>List of avian influenza viruses serially passaged in mice lung and their altered genetic and pathogenic properties after adaptation</title></caption><alternatives><graphic xlink:href="cevr-6-83-i001"></graphic><table frame="hsides" rules="rows"><col width="5.24%" span="1"></col><col width="15.05%" span="1"></col><col width="6.15%" span="1"></col><col width="5.24%" span="1"></col><col width="7.85%" span="1"></col><col width="11.91%" span="1"></col><col width="31.94%" span="1"></col><col width="11.39%" span="1"></col><col width="5.24%" span="1"></col><thead><tr><th valign="middle" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Subtype</th><th valign="middle" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Parental virus</th><th valign="middle" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Pathogenicity index<sup>a)</sup></th><th valign="middle" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Mouse strain</th><th valign="middle" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">No. of passages (detectable virulence<sup>b)</sup>)</th><th valign="middle" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">MLD<sub>50</sub> of MA-variant</th><th valign="middle" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">No. of AA mutations (considerable mutations<sup>c)</sup>)</th><th valign="middle" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Tissue distribution</th><th valign="middle" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Reference</th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="3" colspan="1">H5N1</td><td valign="top" align="left" rowspan="1" colspan="1">Ck/Yamaguchi/7/04</td><td valign="top" align="left" rowspan="1" colspan="1">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1">1 (1)</td><td valign="top" align="center" rowspan="1" colspan="1">0.9 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1">2 (PB2-E627K; HA-M531I)</td><td valign="top" align="center" rowspan="1" colspan="1">Lu, Br, Sp, Li, Ki</td><td valign="top" align="center" rowspan="1" colspan="1">[<xref rid="B31" ref-type="bibr">31</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Wdk/Hunan/021/05</td><td valign="top" align="left" rowspan="1" colspan="1">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1">15 (1)</td><td valign="top" align="center" rowspan="1" colspan="1">0.5-2.2 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1">15 (PB2-E627K, -L89V, -G309D, -T339K, -R477G, -I495V, -A676T)</td><td valign="top" align="center" rowspan="1" colspan="1">Lu, Br, Li, Sp, Ki</td><td valign="top" align="center" rowspan="1" colspan="1">[<xref rid="B27" ref-type="bibr">27</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Vietnam/1203/04</td><td valign="top" align="left" rowspan="1" colspan="1">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1">1 (1)</td><td valign="top" align="center" rowspan="1" colspan="1">ND</td><td valign="top" align="left" rowspan="1" colspan="1">1 (PB2-E627K)</td><td valign="top" align="center" rowspan="1" colspan="1">Respiratory organ</td><td valign="top" align="center" rowspan="1" colspan="1">[<xref rid="B32" ref-type="bibr">32</xref>]</td></tr><tr><td valign="top" align="left" rowspan="4" colspan="1" style="background-color:rgb(255,240,220)">H5N2</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Ck/Hebei/1102/10</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">15 (5)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">2.5 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">5 (PB2-Q591K, D701N)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu, Hr, Li, Sp, Ki, Br</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B47" ref-type="bibr">47</xref>,<xref rid="B82" ref-type="bibr">82</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Dk/Zhejiang/6DK19/13</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">10 (ND)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">ND</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">4 (PB2-E627K; PB1-I181T; HA-A150S; NS2-E69G)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu, Sp, Ki, Li, Br, Hr</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B49" ref-type="bibr">49</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Mdk/Pennsylvania/10218/84</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">ND</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">23 (23)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">1.75 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">3 (HA-L320P, -S203F, -E273G)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B37" ref-type="bibr">37</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">AB/Korea/W81/05</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">17 (10)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">2.7 log<sub>10</sub>TCID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">8 (PB2-E627K; PA-T97I)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B28" ref-type="bibr">28</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">H5N6</td><td valign="top" align="left" rowspan="1" colspan="1">Dk/Zhejiang/6D2/13</td><td valign="top" align="left" rowspan="1" colspan="1">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1">10 (ND)</td><td valign="top" align="center" rowspan="1" colspan="1">2.68 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1">5 (PB2-E627K; PA-A343T; HA-A150V; NA-R143K, -G147E)</td><td valign="top" align="center" rowspan="1" colspan="1">Br, Sp, Li, Ki, Hr, Lu</td><td valign="top" align="center" rowspan="1" colspan="1">[<xref rid="B48" ref-type="bibr">48</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">H5N8</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Mdk/Korea/W452/14<break></break>Em/Korea/W468/15</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">5 (2)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">0.5-4.8 log<sub>10</sub>PFU</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">14 (PB2-E627K, -D701N, -Q591K; PB1-P708S; PA-T97I)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu, Br, Hr, Li, Sp, Int</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B35" ref-type="bibr">35</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">H7N1</td><td valign="top" align="left" rowspan="1" colspan="1">BP/HuNan/414/10</td><td valign="top" align="left" rowspan="1" colspan="1">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1">5 (ND)</td><td valign="top" align="center" rowspan="1" colspan="1">1.75-2.25 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1">6 (PB2-E627K; HA-E114K, -G205E, -G218E; NA-S350N)</td><td valign="top" align="center" rowspan="1" colspan="1">Lu, Br, Li, Sp, Ki, Int</td><td valign="top" align="center" rowspan="1" colspan="1">[<xref rid="B59" ref-type="bibr">59</xref>]</td></tr><tr><td valign="top" align="left" rowspan="3" colspan="1" style="background-color:rgb(255,240,220)">H7N7</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Ck-egg adapted Seal/Massachussetts/1/80</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">11 (ND)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">2.8 log<sub>10</sub>PFU</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">9 (PB2-D701N, S714R; NP-N319K)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B58" ref-type="bibr">58</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Ck/Netherlands/621557/03</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">HPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">3 (3)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">2.7 log<sub>10</sub>TCID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">1 (PB2-E627K)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">NT, Tr, Lu, Ileum, Jejun, Ki, Li, Sp, Hr, Br</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B57" ref-type="bibr">57</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LWFG/HuNan/412/10</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">7 (ND)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">2.75-3.5 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">7 (PB2-E627K; PB1-R118I; PA-L550M; HA-G214R; NA-S372N)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu, Br, Li, Sp, Ki, Int</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B60" ref-type="bibr">60</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">H7N9</td><td valign="top" align="left" rowspan="1" colspan="1">Shanghai/2/2013</td><td valign="top" align="left" rowspan="1" colspan="1">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1">10 (ND)</td><td valign="top" align="center" rowspan="1" colspan="1">1.5-3.5 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1">14 (PA-T97I, K328R; HA-A107T, -L226Q, -R354K; NP-A284T, -M352I; NA-M26I, -G389D)</td><td valign="top" align="center" rowspan="1" colspan="1">Lu, Br, Li, Ki, Sp, Int</td><td valign="top" align="center" rowspan="1" colspan="1">[<xref rid="B61" ref-type="bibr">61</xref>]</td></tr><tr><td valign="top" align="left" rowspan="6" colspan="1" style="background-color:rgb(255,240,220)">H9N2</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Ck/Jiangsu/7/02</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">ND (ND)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">ND</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">25 (PB2-E627K)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Hr, Ki, Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B75" ref-type="bibr">75</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Ck/Hubei/01/99</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">8 (5)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">ND</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">9 (PB2-E627K)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Li, Lu, Sp, Ki, Hr</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B76" ref-type="bibr">76</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Ck/Shandong/16/05</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">8 (8)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">2.8 log<sub>10</sub>PFU</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">5 (PB2-M147L, -E627K)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B77" ref-type="bibr">77</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Dk/Jiangsu/1/08</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">18 (5)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">2.5 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">8 (PB2-F404L)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B78" ref-type="bibr">78</xref>,<xref rid="B79" ref-type="bibr">79</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Ck/Shandong/Li-2/10</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">5 (4)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">3.5 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">3 (PB2-E627K; HA-N313D, -N496S)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B80" ref-type="bibr">80</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Ck/Korea/163/04</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">98 (ND)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">ND</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">23 (PB2-E627K; HA-N158S)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B81" ref-type="bibr">81</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">H6N1</td><td valign="top" align="left" rowspan="1" colspan="1">Mdk/SanJiang/275/07</td><td valign="top" align="left" rowspan="1" colspan="1">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1">8 (ND)</td><td valign="top" align="center" rowspan="1" colspan="1">2.75 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1">3 (PB2-E627K; PA-T97I)</td><td valign="top" align="center" rowspan="1" colspan="1">Lu, Br</td><td valign="top" align="center" rowspan="1" colspan="1">[<xref rid="B83" ref-type="bibr">83</xref>]</td></tr><tr><td valign="top" align="left" rowspan="2" colspan="1" style="background-color:rgb(255,240,220)">H6N6</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Sw/Guangdong/K6/10</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">12 (8)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">3.89 log<sub>10</sub>PFU</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">5 (HA-H156N, -S263R; PA-I38M; PB2-E627K)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B84" ref-type="bibr">84</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Dk/Hubei/5/10</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">8 (4)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">3.4 log<sub>10</sub>EID<sub>50</sub></td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">17 (PB2-E627K)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Lu, Sp, Ki</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B85" ref-type="bibr">85</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">H10N7</td><td valign="top" align="left" rowspan="1" colspan="1">Ck/Zhejiang/2CP8/14</td><td valign="top" align="left" rowspan="1" colspan="1">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1">10 (9)</td><td valign="top" align="center" rowspan="1" colspan="1">ND</td><td valign="top" align="left" rowspan="1" colspan="1">3 (PB2-E627K; PA-T97I)</td><td valign="top" align="center" rowspan="1" colspan="1">Lu, Br, Li, Ki, Sp, Hr</td><td valign="top" align="center" rowspan="1" colspan="1">[<xref rid="B38" ref-type="bibr">38</xref>]</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">H10N8</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">Em/Hunan/3-9/07</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">LPAI</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">BALB/c</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">7 (3)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">ND</td><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">7 (PB2-E627K; PA-F277S, -C278Q)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">multiple organs</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(255,240,220)">[<xref rid="B86" ref-type="bibr">86</xref>]</td></tr></tbody></table></alternatives><table-wrap-foot><fn><p><sup>a)</sup>Defined by intravenous pathogenicity index criteria.</p><p><sup>b)</sup>The number of lung passages showing detectable virulence in mice.</p><p><sup>c)</sup>Mutations that the authors mentioned or proved important.</p><p>MLD, mouse lethal dose; MA, mouse-adapted; Ck, chicken; HPAI, highly pathogenic avian influenza; EID, egg infectious dose; Lu, lung; Br, brain; Sp, spleen; Li, liver; Ki, kidney; ND, not determined/defined; NS, not specified; Hr, heart; LPAI, low pathogenic avian influenza; TCID, tissue cultured infectious dose; Dk, duck; Mdk, mallard duck; PFU, plaque forming unit; Em, environment; Int, intestine; BP, Baer's Pochard; NT, nasal turbinate; Tr, trachea; LWFG, Lesser White-fronted Goose; Sw, swine.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/H2N2V1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000D15 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000D15 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= H2N2V1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:5540968
|texte= The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:28775972" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a H2N2V1
| This area was generated with Dilib version V0.6.33. |  |