Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden
Identifieur interne : 006F08 ( Ncbi/Merge ); précédent : 006F07; suivant : 006F09Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden
Auteurs : Jessica C. Jang [États-Unis] ; Gang Chen [États-Unis] ; Spencer H. Wang [États-Unis] ; Mark A. Barnes [États-Unis] ; Josiah I. Chung [États-Unis] ; Mali Camberis [Nouvelle-Zélande] ; Graham Le Gros [Nouvelle-Zélande] ; Philip J. Cooper [Équateur, Royaume-Uni] ; Cathy Steel [États-Unis] ; Thomas B. Nutman [États-Unis] ; Mitchell A. Lazar [États-Unis] ; Meera G. Nair [États-Unis]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2015.
Abstract
Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (h
Url:
DOI: 10.1371/journal.ppat.1004579
PubMed: 25568944
PubMed Central: 4287580
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Jang</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Chen, Gang" sort="Chen, Gang" uniqKey="Chen G" first="Gang" last="Chen">Gang Chen</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Wang, Spencer H" sort="Wang, Spencer H" uniqKey="Wang S" first="Spencer H." last="Wang">Spencer H. 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Chung</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Camberis, Mali" sort="Camberis, Mali" uniqKey="Camberis M" first="Mali" last="Camberis">Mali Camberis</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Malaghan Institute of Medical Research, Wellington, New Zealand</addr-line></nlm:aff><country xml:lang="fr">Nouvelle-Zélande</country><wicri:regionArea>Malaghan Institute of Medical Research, Wellington</wicri:regionArea><wicri:noRegion>Wellington</wicri:noRegion></affiliation></author><author><name sortKey="Le Gros, Graham" sort="Le Gros, Graham" uniqKey="Le Gros G" first="Graham" last="Le Gros">Graham Le Gros</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Malaghan Institute of Medical Research, Wellington, New Zealand</addr-line></nlm:aff><country xml:lang="fr">Nouvelle-Zélande</country><wicri:regionArea>Malaghan Institute of Medical Research, Wellington</wicri:regionArea><wicri:noRegion>Wellington</wicri:noRegion></affiliation></author><author><name sortKey="Cooper, Philip J" sort="Cooper, Philip J" uniqKey="Cooper P" first="Philip J." last="Cooper">Philip J. 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Nutman</name><affiliation wicri:level="2"><nlm:aff id="aff6"><addr-line>Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Lazar, Mitchell A" sort="Lazar, Mitchell A" uniqKey="Lazar M" first="Mitchell A." last="Lazar">Mitchell A. Lazar</name><affiliation wicri:level="2"><nlm:aff id="aff7"><addr-line>Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Nair, Meera G" sort="Nair, Meera G" uniqKey="Nair M" first="Meera G." last="Nair">Meera G. Nair</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (h<italic>Retn</italic>Tg<sup>+</sup>). Following infection with the helminth <italic>Nippostrongylus brasiliensis</italic> (<italic>Nb</italic>), hResistin expression was significantly upregulated in infected tissue. Compared to control h<italic>Retn</italic>Tg<sup>−</sup> mice, h<italic>Retn</italic>Tg<sup>+</sup> mice suffered from exacerbated <italic>Nb</italic>-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated <italic>Nb</italic> egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode <italic>Wuchereria bancrofti</italic>, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hotez, Pj" uniqKey="Hotez P">PJ Hotez</name></author><author><name sortKey="Brindley, Pj" uniqKey="Brindley P">PJ Brindley</name></author><author><name sortKey="Bethony, Jm" uniqKey="Bethony J">JM Bethony</name></author><author><name sortKey="King, Ch" uniqKey="King C">CH King</name></author><author><name sortKey="Pearce, Ej" uniqKey="Pearce E">EJ Pearce</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Macdonald, Tt" uniqKey="Macdonald T">TT MacDonald</name></author><author><name sortKey="Choy, My" uniqKey="Choy M">MY Choy</name></author><author><name sortKey="Spencer, J" uniqKey="Spencer J">J Spencer</name></author><author><name sortKey="Richman, Pi" uniqKey="Richman P">PI Richman</name></author><author><name sortKey="Diss, T" uniqKey="Diss T">T Diss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Min, B" uniqKey="Min B">B Min</name></author><author><name sortKey="Prout, M" uniqKey="Prout M">M Prout</name></author><author><name sortKey="Hu Li, J" uniqKey="Hu Li J">J Hu-Li</name></author><author><name sortKey="Zhu, J" uniqKey="Zhu J">J Zhu</name></author><author><name sortKey="Jankovic, D" uniqKey="Jankovic D">D Jankovic</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Neill, Dr" uniqKey="Neill D">DR Neill</name></author><author><name sortKey="Wong, Sh" uniqKey="Wong S">SH Wong</name></author><author><name sortKey="Bellosi, A" uniqKey="Bellosi A">A Bellosi</name></author><author><name sortKey="Flynn, Rj" uniqKey="Flynn R">RJ Flynn</name></author><author><name sortKey="Daly, M" uniqKey="Daly M">M Daly</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Voehringer, D" uniqKey="Voehringer D">D Voehringer</name></author><author><name sortKey="Shinkai, K" uniqKey="Shinkai K">K Shinkai</name></author><author><name sortKey="Locksley, Rm" uniqKey="Locksley R">RM Locksley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Le Goff, L" uniqKey="Le Goff L">L Le Goff</name></author><author><name sortKey="Lamb, Tj" uniqKey="Lamb T">TJ Lamb</name></author><author><name sortKey="Graham, Al" uniqKey="Graham A">AL Graham</name></author><author><name sortKey="Harcus, Y" uniqKey="Harcus Y">Y Harcus</name></author><author><name sortKey="Allen, Je" uniqKey="Allen J">JE Allen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Urban, Jf" uniqKey="Urban J">JF Urban</name></author><author><name sortKey="Noben Trauth, N" uniqKey="Noben Trauth N">N Noben-Trauth</name></author><author><name sortKey="Donaldson, Dd" uniqKey="Donaldson D">DD Donaldson</name></author><author><name sortKey="Madden, Kb" uniqKey="Madden K">KB Madden</name></author><author><name sortKey="Morris, Sc" uniqKey="Morris S">SC Morris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, F" uniqKey="Chen F">F Chen</name></author><author><name sortKey="Liu, Z" uniqKey="Liu Z">Z Liu</name></author><author><name sortKey="Wu, W" uniqKey="Wu W">W Wu</name></author><author><name sortKey="Rozo, C" uniqKey="Rozo C">C Rozo</name></author><author><name sortKey="Bowdridge, S" uniqKey="Bowdridge S">S Bowdridge</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Herbert, Dr" uniqKey="Herbert D">DR Herbert</name></author><author><name sortKey="Holscher, C" uniqKey="Holscher C">C Holscher</name></author><author><name sortKey="Mohrs, M" uniqKey="Mohrs M">M Mohrs</name></author><author><name sortKey="Arendse, B" uniqKey="Arendse B">B Arendse</name></author><author><name sortKey="Schwegmann, A" uniqKey="Schwegmann A">A Schwegmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Urban, J" uniqKey="Urban J">J Urban</name></author><author><name sortKey="Fang, H" uniqKey="Fang H">H Fang</name></author><author><name sortKey="Liu, Q" uniqKey="Liu Q">Q Liu</name></author><author><name sortKey="Ekkens, Mj" uniqKey="Ekkens M">MJ Ekkens</name></author><author><name sortKey="Chen, Sj" uniqKey="Chen S">SJ Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Babu, S" uniqKey="Babu S">S Babu</name></author><author><name sortKey="Bhat, Sq" uniqKey="Bhat S">SQ Bhat</name></author><author><name sortKey="Pavan Kumar, N" uniqKey="Pavan Kumar N">N Pavan Kumar</name></author><author><name sortKey="Lipira, Ab" uniqKey="Lipira A">AB Lipira</name></author><author><name sortKey="Kumar, S" uniqKey="Kumar S">S Kumar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Babu, S" uniqKey="Babu S">S Babu</name></author><author><name sortKey="Anuradha, R" uniqKey="Anuradha R">R Anuradha</name></author><author><name sortKey="Kumar, Np" uniqKey="Kumar N">NP Kumar</name></author><author><name sortKey="George, Pj" uniqKey="George P">PJ George</name></author><author><name sortKey="Kumaraswami, V" uniqKey="Kumaraswami V">V Kumaraswami</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Helmby, H" uniqKey="Helmby H">H Helmby</name></author><author><name sortKey="Grencis, Rk" uniqKey="Grencis R">RK Grencis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Rz" uniqKey="Yang R">RZ Yang</name></author><author><name sortKey="Huang, Q" uniqKey="Huang Q">Q Huang</name></author><author><name sortKey="Xu, A" uniqKey="Xu A">A Xu</name></author><author><name sortKey="Mclenithan, Jc" uniqKey="Mclenithan J">JC McLenithan</name></author><author><name sortKey="Eisen, Ja" uniqKey="Eisen J">JA Eisen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nair, Mg" uniqKey="Nair M">MG Nair</name></author><author><name sortKey="Du, Y" uniqKey="Du Y">Y Du</name></author><author><name sortKey="Perrigoue, Jg" uniqKey="Perrigoue J">JG Perrigoue</name></author><author><name sortKey="Zaph, C" uniqKey="Zaph C">C Zaph</name></author><author><name sortKey="Taylor, Jj" uniqKey="Taylor J">JJ Taylor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pesce, Jt" uniqKey="Pesce J">JT Pesce</name></author><author><name sortKey="Ramalingam, Tr" uniqKey="Ramalingam T">TR Ramalingam</name></author><author><name sortKey="Wilson, Ms" uniqKey="Wilson M">MS Wilson</name></author><author><name sortKey="Mentink Kane, Mm" uniqKey="Mentink Kane M">MM Mentink-Kane</name></author><author><name sortKey="Thompson, Rw" uniqKey="Thompson R">RW Thompson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nair, Mg" uniqKey="Nair M">MG Nair</name></author><author><name sortKey="Guild, Kj" uniqKey="Guild K">KJ Guild</name></author><author><name sortKey="Du, Y" uniqKey="Du Y">Y Du</name></author><author><name sortKey="Zaph, C" uniqKey="Zaph C">C Zaph</name></author><author><name sortKey="Yancopoulos, Gd" uniqKey="Yancopoulos G">GD Yancopoulos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Artis, D" uniqKey="Artis D">D Artis</name></author><author><name sortKey="Wang, Ml" uniqKey="Wang M">ML Wang</name></author><author><name sortKey="Keilbaugh, Sa" uniqKey="Keilbaugh S">SA Keilbaugh</name></author><author><name sortKey="He, W" uniqKey="He W">W He</name></author><author><name sortKey="Brenes, M" uniqKey="Brenes M">M Brenes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Steppan, Cm" uniqKey="Steppan C">CM Steppan</name></author><author><name sortKey="Bailey, St" uniqKey="Bailey S">ST Bailey</name></author><author><name sortKey="Bhat, S" uniqKey="Bhat S">S Bhat</name></author><author><name sortKey="Brown, Ej" uniqKey="Brown E">EJ Brown</name></author><author><name sortKey="Banerjee, Rr" uniqKey="Banerjee R">RR Banerjee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jung, Hs" uniqKey="Jung H">HS Jung</name></author><author><name sortKey="Park, Kh" uniqKey="Park K">KH Park</name></author><author><name sortKey="Cho, Ym" uniqKey="Cho Y">YM Cho</name></author><author><name sortKey="Chung, Ss" uniqKey="Chung S">SS Chung</name></author><author><name sortKey="Cho, Hj" uniqKey="Cho H">HJ Cho</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Patel, L" uniqKey="Patel L">L Patel</name></author><author><name sortKey="Buckels, Ac" uniqKey="Buckels A">AC Buckels</name></author><author><name sortKey="Kinghorn, Ij" uniqKey="Kinghorn I">IJ Kinghorn</name></author><author><name sortKey="Murdock, Pr" uniqKey="Murdock P">PR Murdock</name></author><author><name sortKey="Holbrook, Jd" uniqKey="Holbrook J">JD Holbrook</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Migita, K" uniqKey="Migita K">K Migita</name></author><author><name sortKey="Maeda, Y" uniqKey="Maeda Y">Y Maeda</name></author><author><name sortKey="Miyashita, T" uniqKey="Miyashita T">T Miyashita</name></author><author><name sortKey="Kimura, H" uniqKey="Kimura H">H Kimura</name></author><author><name sortKey="Nakamura, M" uniqKey="Nakamura M">M Nakamura</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reilly, Mp" uniqKey="Reilly M">MP Reilly</name></author><author><name sortKey="Lehrke, M" uniqKey="Lehrke M">M Lehrke</name></author><author><name sortKey="Wolfe, Ml" uniqKey="Wolfe M">ML Wolfe</name></author><author><name sortKey="Rohatgi, A" uniqKey="Rohatgi A">A Rohatgi</name></author><author><name sortKey="Lazar, Ma" uniqKey="Lazar M">MA Lazar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jiang, S" uniqKey="Jiang S">S Jiang</name></author><author><name sortKey="Park, Dw" uniqKey="Park D">DW Park</name></author><author><name sortKey="Tadie, Jm" uniqKey="Tadie J">JM Tadie</name></author><author><name sortKey="Gregoire, M" uniqKey="Gregoire M">M Gregoire</name></author><author><name sortKey="Deshane, J" uniqKey="Deshane J">J Deshane</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lehrke, M" uniqKey="Lehrke M">M Lehrke</name></author><author><name sortKey="Reilly, Mp" uniqKey="Reilly M">MP Reilly</name></author><author><name sortKey="Millington, Sc" uniqKey="Millington S">SC Millington</name></author><author><name sortKey="Iqbal, N" uniqKey="Iqbal N">N Iqbal</name></author><author><name sortKey="Rader, Dj" uniqKey="Rader D">DJ Rader</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, Hk" uniqKey="Park H">HK Park</name></author><author><name sortKey="Qatanani, M" uniqKey="Qatanani M">M Qatanani</name></author><author><name sortKey="Briggs, Er" uniqKey="Briggs E">ER Briggs</name></author><author><name sortKey="Ahima, Rs" uniqKey="Ahima R">RS Ahima</name></author><author><name sortKey="Lazar, Ma" uniqKey="Lazar M">MA Lazar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuo, Ch" uniqKey="Kuo C">CH Kuo</name></author><author><name sortKey="Chen, Kf" uniqKey="Chen K">KF Chen</name></author><author><name sortKey="Chou, Sh" uniqKey="Chou S">SH Chou</name></author><author><name sortKey="Huang, Yf" uniqKey="Huang Y">YF Huang</name></author><author><name sortKey="Wu, Cy" uniqKey="Wu C">CY Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hsieh, Yy" uniqKey="Hsieh Y">YY Hsieh</name></author><author><name sortKey="Shen, Ch" uniqKey="Shen C">CH Shen</name></author><author><name sortKey="Huang, Ws" uniqKey="Huang W">WS Huang</name></author><author><name sortKey="Chin, Cc" uniqKey="Chin C">CC Chin</name></author><author><name sortKey="Kuo, Yh" uniqKey="Kuo Y">YH Kuo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Benomar, Y" uniqKey="Benomar Y">Y Benomar</name></author><author><name sortKey="Gertler, A" uniqKey="Gertler A">A Gertler</name></author><author><name sortKey="De Lacy, P" uniqKey="De Lacy P">P De Lacy</name></author><author><name sortKey="Crepin, D" uniqKey="Crepin D">D Crepin</name></author><author><name sortKey="Ould Hamouda, H" uniqKey="Ould Hamouda H">H Ould Hamouda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reece, Jj" uniqKey="Reece J">JJ Reece</name></author><author><name sortKey="Siracusa, Mc" uniqKey="Siracusa M">MC Siracusa</name></author><author><name sortKey="Scott, Al" uniqKey="Scott A">AL Scott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boring, L" uniqKey="Boring L">L Boring</name></author><author><name sortKey="Gosling, J" uniqKey="Gosling J">J Gosling</name></author><author><name sortKey="Chensue, Sw" uniqKey="Chensue S">SW Chensue</name></author><author><name sortKey="Kunkel, Sl" uniqKey="Kunkel S">SL Kunkel</name></author><author><name sortKey="Farese, Rv" uniqKey="Farese R">RV Farese</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Taub, Dd" uniqKey="Taub D">DD Taub</name></author><author><name sortKey="Lloyd, Ar" uniqKey="Lloyd A">AR Lloyd</name></author><author><name sortKey="Conlon, K" uniqKey="Conlon K">K Conlon</name></author><author><name sortKey="Wang, Jm" uniqKey="Wang J">JM Wang</name></author><author><name sortKey="Ortaldo, Jr" uniqKey="Ortaldo J">JR Ortaldo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Odegaard, Ji" uniqKey="Odegaard J">JI Odegaard</name></author><author><name sortKey="Chawla, A" uniqKey="Chawla A">A Chawla</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thomas, Gd" uniqKey="Thomas G">GD Thomas</name></author><author><name sortKey="Ruckerl, D" uniqKey="Ruckerl D">D Ruckerl</name></author><author><name sortKey="Maskrey, Bh" uniqKey="Maskrey B">BH Maskrey</name></author><author><name sortKey="Whitfield, Pd" uniqKey="Whitfield P">PD Whitfield</name></author><author><name sortKey="Blaxter, Ml" uniqKey="Blaxter M">ML Blaxter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lehrke, M" uniqKey="Lehrke M">M Lehrke</name></author><author><name sortKey="Lazar, Ma" uniqKey="Lazar M">MA Lazar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jackson, Ja" uniqKey="Jackson J">JA Jackson</name></author><author><name sortKey="Turner, Jd" uniqKey="Turner J">JD Turner</name></author><author><name sortKey="Kamal, M" uniqKey="Kamal M">M Kamal</name></author><author><name sortKey="Wright, V" uniqKey="Wright V">V Wright</name></author><author><name sortKey="Bickle, Q" uniqKey="Bickle Q">Q Bickle</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bethony, J" uniqKey="Bethony J">J Bethony</name></author><author><name sortKey="Brooker, S" uniqKey="Brooker S">S Brooker</name></author><author><name sortKey="Albonico, M" uniqKey="Albonico M">M Albonico</name></author><author><name sortKey="Geiger, Sm" uniqKey="Geiger S">SM Geiger</name></author><author><name sortKey="Loukas, A" uniqKey="Loukas A">A Loukas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moncayo, Al" uniqKey="Moncayo A">AL Moncayo</name></author><author><name sortKey="Vaca, M" uniqKey="Vaca M">M Vaca</name></author><author><name sortKey="Oviedo, G" uniqKey="Oviedo G">G Oviedo</name></author><author><name sortKey="Workman, Lj" uniqKey="Workman L">LJ Workman</name></author><author><name sortKey="Chico, Me" uniqKey="Chico M">ME Chico</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Loke, P" uniqKey="Loke P">P Loke</name></author><author><name sortKey="Nair, Mg" uniqKey="Nair M">MG Nair</name></author><author><name sortKey="Parkinson, J" uniqKey="Parkinson J">J Parkinson</name></author><author><name sortKey="Guiliano, D" uniqKey="Guiliano D">D Guiliano</name></author><author><name sortKey="Blaxter, M" uniqKey="Blaxter M">M Blaxter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nair, Mg" uniqKey="Nair M">MG Nair</name></author><author><name sortKey="Gallagher, Ij" uniqKey="Gallagher I">IJ Gallagher</name></author><author><name sortKey="Taylor, Md" uniqKey="Taylor M">MD Taylor</name></author><author><name sortKey="Loke, P" uniqKey="Loke P">P Loke</name></author><author><name sortKey="Coulson, Ps" uniqKey="Coulson P">PS Coulson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cuenco, Kt" uniqKey="Cuenco K">KT Cuenco</name></author><author><name sortKey="Ottesen, Ea" uniqKey="Ottesen E">EA Ottesen</name></author><author><name sortKey="Williams, Sa" uniqKey="Williams S">SA Williams</name></author><author><name sortKey="Nutman, Tb" uniqKey="Nutman T">TB Nutman</name></author><author><name sortKey="Steel, C" uniqKey="Steel C">C Steel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weller, Pf" uniqKey="Weller P">PF Weller</name></author><author><name sortKey="Ottesen, Ea" uniqKey="Ottesen E">EA Ottesen</name></author><author><name sortKey="Heck, L" uniqKey="Heck L">L Heck</name></author><author><name sortKey="Tere, T" uniqKey="Tere T">T Tere</name></author><author><name sortKey="Neva, Fa" uniqKey="Neva F">FA Neva</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Anthony, Rm" uniqKey="Anthony R">RM Anthony</name></author><author><name sortKey="Rutitzky, Li" uniqKey="Rutitzky L">LI Rutitzky</name></author><author><name sortKey="Urban, Jf" uniqKey="Urban J">JF Urban</name></author><author><name sortKey="Stadecker, Mj" uniqKey="Stadecker M">MJ Stadecker</name></author><author><name sortKey="Gause, Wc" uniqKey="Gause W">WC Gause</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Herbert, Dr" uniqKey="Herbert D">DR Herbert</name></author><author><name sortKey="Yang, Jq" uniqKey="Yang J">JQ Yang</name></author><author><name sortKey="Hogan, Sp" uniqKey="Hogan S">SP Hogan</name></author><author><name sortKey="Groschwitz, K" uniqKey="Groschwitz K">K Groschwitz</name></author><author><name sortKey="Khodoun, M" uniqKey="Khodoun M">M Khodoun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="He, W" uniqKey="He W">W He</name></author><author><name sortKey="Wang, Ml" uniqKey="Wang M">ML Wang</name></author><author><name sortKey="Jiang, Hq" uniqKey="Jiang H">HQ Jiang</name></author><author><name sortKey="Steppan, Cm" uniqKey="Steppan C">CM Steppan</name></author><author><name sortKey="Shin, Me" uniqKey="Shin M">ME Shin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Osborne, Lc" uniqKey="Osborne L">LC Osborne</name></author><author><name sortKey="Joyce, Kl" uniqKey="Joyce K">KL Joyce</name></author><author><name sortKey="Alenghat, T" uniqKey="Alenghat T">T Alenghat</name></author><author><name sortKey="Sonnenberg, Gf" uniqKey="Sonnenberg G">GF Sonnenberg</name></author><author><name sortKey="Giacomin, Pr" uniqKey="Giacomin P">PR Giacomin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Qatanani, M" uniqKey="Qatanani M">M Qatanani</name></author><author><name sortKey="Szwergold, Nr" uniqKey="Szwergold N">NR Szwergold</name></author><author><name sortKey="Greaves, Dr" uniqKey="Greaves D">DR Greaves</name></author><author><name sortKey="Ahima, Rs" uniqKey="Ahima R">RS Ahima</name></author><author><name sortKey="Lazar, Ma" uniqKey="Lazar M">MA Lazar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Babu, S" uniqKey="Babu S">S Babu</name></author><author><name sortKey="Kumaraswami, V" uniqKey="Kumaraswami V">V Kumaraswami</name></author><author><name sortKey="Nutman, Tb" uniqKey="Nutman T">TB Nutman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Semnani, Rt" uniqKey="Semnani R">RT Semnani</name></author><author><name sortKey="Mahapatra, L" uniqKey="Mahapatra L">L Mahapatra</name></author><author><name sortKey="Moore, V" uniqKey="Moore V">V Moore</name></author><author><name sortKey="Sanprasert, V" uniqKey="Sanprasert V">V Sanprasert</name></author><author><name sortKey="Nutman, Tb" uniqKey="Nutman T">TB Nutman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gan, Am" uniqKey="Gan A">AM Gan</name></author><author><name sortKey="Butoi, Ed" uniqKey="Butoi E">ED Butoi</name></author><author><name sortKey="Manea, A" uniqKey="Manea A">A Manea</name></author><author><name sortKey="Simion, V" uniqKey="Simion V">V Simion</name></author><author><name sortKey="Stan, D" uniqKey="Stan D">D Stan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Silswal, N" uniqKey="Silswal N">N Silswal</name></author><author><name sortKey="Singh, Ak" uniqKey="Singh A">AK Singh</name></author><author><name sortKey="Aruna, B" uniqKey="Aruna B">B Aruna</name></author><author><name sortKey="Mukhopadhyay, S" uniqKey="Mukhopadhyay S">S Mukhopadhyay</name></author><author><name sortKey="Ghosh, S" uniqKey="Ghosh S">S Ghosh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tarkowski, A" uniqKey="Tarkowski A">A Tarkowski</name></author><author><name sortKey="Bjersing, J" uniqKey="Bjersing J">J Bjersing</name></author><author><name sortKey="Shestakov, A" uniqKey="Shestakov A">A Shestakov</name></author><author><name sortKey="Bokarewa, Mi" uniqKey="Bokarewa M">MI Bokarewa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pirvulescu, Mm" uniqKey="Pirvulescu M">MM Pirvulescu</name></author><author><name sortKey="Gan, Am" uniqKey="Gan A">AM Gan</name></author><author><name sortKey="Stan, D" uniqKey="Stan D">D Stan</name></author><author><name sortKey="Simion, V" uniqKey="Simion V">V Simion</name></author><author><name sortKey="Calin, M" uniqKey="Calin M">M Calin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, S" uniqKey="Lee S">S Lee</name></author><author><name sortKey="Lee, Hc" uniqKey="Lee H">HC Lee</name></author><author><name sortKey="Kwon, Yw" uniqKey="Kwon Y">YW Kwon</name></author><author><name sortKey="Lee, Se" uniqKey="Lee S">SE Lee</name></author><author><name sortKey="Cho, Y" uniqKey="Cho Y">Y Cho</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Anuradha, R" uniqKey="Anuradha R">R Anuradha</name></author><author><name sortKey="George, Pj" uniqKey="George P">PJ George</name></author><author><name sortKey="Pavan Kumar, N" uniqKey="Pavan Kumar N">N Pavan Kumar</name></author><author><name sortKey="Fay, Mp" uniqKey="Fay M">MP Fay</name></author><author><name sortKey="Kumaraswami, V" uniqKey="Kumaraswami V">V Kumaraswami</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="George, Pj" uniqKey="George P">PJ George</name></author><author><name sortKey="Anuradha, R" uniqKey="Anuradha R">R Anuradha</name></author><author><name sortKey="Kumar, Np" uniqKey="Kumar N">NP Kumar</name></author><author><name sortKey="Kumaraswami, V" uniqKey="Kumaraswami V">V Kumaraswami</name></author><author><name sortKey="Nutman, Tb" uniqKey="Nutman T">TB Nutman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Babu, S" uniqKey="Babu S">S Babu</name></author><author><name sortKey="Nutman, Tb" uniqKey="Nutman T">TB Nutman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, J" uniqKey="Wang J">J Wang</name></author><author><name sortKey="Gusti, V" uniqKey="Gusti V">V Gusti</name></author><author><name sortKey="Saraswati, A" uniqKey="Saraswati A">A Saraswati</name></author><author><name sortKey="Lo, Dd" uniqKey="Lo D">DD Lo</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plospath</journal-id><journal-title-group><journal-title>PLoS Pathogens</journal-title></journal-title-group><issn pub-type="ppub">1553-7366</issn><issn pub-type="epub">1553-7374</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25568944</article-id><article-id pub-id-type="pmc">4287580</article-id><article-id pub-id-type="publisher-id">PPATHOGENS-D-14-01916</article-id><article-id pub-id-type="doi">10.1371/journal.ppat.1004579</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine and Health Sciences</subject><subj-group><subject>Infectious Diseases</subject></subj-group><subj-group><subject>Parasitic Diseases</subject></subj-group></subj-group></article-categories><title-group><article-title>Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden</article-title><alt-title alt-title-type="running-head">Human Resistin in Helminth Infection</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Jang</surname><given-names>Jessica C.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Gang</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Spencer H.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Barnes</surname><given-names>Mark A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chung</surname><given-names>Josiah I.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Camberis</surname><given-names>Mali</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Le Gros</surname><given-names>Graham</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cooper</surname><given-names>Philip J.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Steel</surname><given-names>Cathy</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nutman</surname><given-names>Thomas B.</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lazar</surname><given-names>Mitchell A.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nair</surname><given-names>Meera G.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California, United States of America</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Malaghan Institute of Medical Research, Wellington, New Zealand</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Laboratorio de Investigaciones FEPIS, Quinindé, Ecuador</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Centro de Investigación en Enfermedades Infecciosas, Pontificia Universidad Católica del Ecuador, Quito, Ecuador</addr-line></aff><aff id="aff5"><label>5</label><addr-line>St George's University of London, London, United Kingdom</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, Maryland, United States of America</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Pearce</surname><given-names>Edward J.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Washington University, United States of America</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>meera.nair@ucr.edu</email></corresp><fn fn-type="COI-statement"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: JCJ MGN. Performed the experiments: JCJ GC SHW MAB JIC MGN. Analyzed the data: JCJ MGN CS. Contributed reagents/materials/analysis tools: GLG MC PJC CS TBN MAL. Wrote the paper: JCJ MGN.</p></fn></author-notes><pub-date pub-type="collection"><month>1</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>8</day><month>1</month><year>2015</year></pub-date><volume>11</volume><issue>1</issue><elocation-id>e1004579</elocation-id><history><date date-type="received"><day>7</day><month>8</month><year>2014</year></date><date date-type="accepted"><day>14</day><month>11</month><year>2014</year></date></history><permissions><copyright-year>2015</copyright-year><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</license-p></license></permissions><abstract><p>Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (h<italic>Retn</italic>Tg<sup>+</sup>). Following infection with the helminth <italic>Nippostrongylus brasiliensis</italic> (<italic>Nb</italic>), hResistin expression was significantly upregulated in infected tissue. Compared to control h<italic>Retn</italic>Tg<sup>−</sup> mice, h<italic>Retn</italic>Tg<sup>+</sup> mice suffered from exacerbated <italic>Nb</italic>-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated <italic>Nb</italic> egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode <italic>Wuchereria bancrofti</italic>, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>Parasitic helminths, which infect an estimated two billion people worldwide, represent a significant global public health problem. Infection is associated with life-long morbidity including growth retardation and organ failure. Despite these debilitating conditions, there are currently no successful vaccines against helminths. Further, great variability in the host immune response to helminths exists, with the ability of some individuals to develop immunity, while others are susceptible when re-exposed or maintain life-long chronic infections. Identifying new factors that are differentially expressed in immune versus susceptible individuals could provide new targeting strategies for diagnosis or treatment of helminth infection. Here, we identify an important immunoregulatory function for human resistin in helminth infection. Employing transgenic mice in which the human resistin gene was inserted, we show that human resistin is induced by infection with the helminth <italic>Nippostrongylus brasiliensis</italic>, where it promotes excessive inflammation and impedes parasite killing. Moreover, analysis of clinical samples from two cohorts of individuals infected with filarial nematodes or soil-transmitted helminths revealed increased resistin and serum proinflammatory cytokines compared to putatively immune individuals. Together, these studies suggest that human resistin is a detrimental cytokine that is expressed in multiple helminth infections, mediates pathogenic inflammation, and delays parasite clearance.</p></abstract><funding-group><funding-statement>These studies were supported by the NIH (1R01AI091759-01A1 to MGN; P01DK49210 to MAL), by the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (to CS and TBN), UCR School of Medicine initial complement and Academic Senate grant to MGN, the Health Research Council of New Zealand (to GLG) and the Wellcome Trust (088862/Z/09/Z to PJC). The UCR NextGen sequencing and bioinformatics core (IIGB) are supported by NIH 1S10OD016290-01A1, MRI-1429826 and NIH 1S10RR028934-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="14"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files except for the RNAseq data which is available on GEO under the accession number GSE90537.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files except for the RNAseq data which is available on GEO under the accession number GSE90537.</p></notes></front></pmc><affiliations><list><country><li>Nouvelle-Zélande</li><li>Royaume-Uni</li><li>Équateur</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Californie</li><li>Grand Londres</li><li>Maryland</li><li>Pennsylvanie</li></region><settlement><li>Londres</li></settlement><orgName><li>Université de Londres</li></orgName></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Jang, Jessica C" sort="Jang, Jessica C" uniqKey="Jang J" first="Jessica C." last="Jang">Jessica C. Jang</name></region><name sortKey="Barnes, Mark A" sort="Barnes, Mark A" uniqKey="Barnes M" first="Mark A." last="Barnes">Mark A. Barnes</name><name sortKey="Chen, Gang" sort="Chen, Gang" uniqKey="Chen G" first="Gang" last="Chen">Gang Chen</name><name sortKey="Chung, Josiah I" sort="Chung, Josiah I" uniqKey="Chung J" first="Josiah I." last="Chung">Josiah I. Chung</name><name sortKey="Lazar, Mitchell A" sort="Lazar, Mitchell A" uniqKey="Lazar M" first="Mitchell A." last="Lazar">Mitchell A. Lazar</name><name sortKey="Nair, Meera G" sort="Nair, Meera G" uniqKey="Nair M" first="Meera G." last="Nair">Meera G. Nair</name><name sortKey="Nutman, Thomas B" sort="Nutman, Thomas B" uniqKey="Nutman T" first="Thomas B." last="Nutman">Thomas B. Nutman</name><name sortKey="Steel, Cathy" sort="Steel, Cathy" uniqKey="Steel C" first="Cathy" last="Steel">Cathy Steel</name><name sortKey="Wang, Spencer H" sort="Wang, Spencer H" uniqKey="Wang S" first="Spencer H." last="Wang">Spencer H. Wang</name></country><country name="Nouvelle-Zélande"><noRegion><name sortKey="Camberis, Mali" sort="Camberis, Mali" uniqKey="Camberis M" first="Mali" last="Camberis">Mali Camberis</name></noRegion><name sortKey="Le Gros, Graham" sort="Le Gros, Graham" uniqKey="Le Gros G" first="Graham" last="Le Gros">Graham Le Gros</name></country><country name="Équateur"><noRegion><name sortKey="Cooper, Philip J" sort="Cooper, Philip J" uniqKey="Cooper P" first="Philip J." last="Cooper">Philip J. Cooper</name></noRegion><name sortKey="Cooper, Philip J" sort="Cooper, Philip J" uniqKey="Cooper P" first="Philip J." last="Cooper">Philip J. Cooper</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Cooper, Philip J" sort="Cooper, Philip J" uniqKey="Cooper P" first="Philip J." last="Cooper">Philip J. Cooper</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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