Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis.
Identifieur interne : 000A60 ( PubMed/Corpus ); précédent : 000A59; suivant : 000A61Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis.
Auteurs : Vineet D. Menachery ; Lisa E. Gralinski ; Hugh D. Mitchell ; Kenneth H. Dinnon ; Sarah R. Leist ; Boyd L. Yount ; Rachel L. Graham ; Eileen T. Mcanarney ; Kelly G. Stratton ; Adam S. Cockrell ; Kari Debbink ; Amy C. Sims ; Katrina M. Waters ; Ralph S. BaricSource :
- mSphere [ 2379-5042 ]
Abstract
Coronaviruses (CoVs) encode a mixture of highly conserved and novel genes, as well as genetic elements necessary for infection and pathogenesis, raising the possibility of common targets for attenuation and therapeutic design. In this study, we focused on highly conserved nonstructural protein 16 (NSP16), a viral 2'O-methyltransferase (2'O-MTase) that encodes critical functions in immune modulation and infection. Using reverse genetics, we disrupted a key motif in the conserved KDKE motif of Middle East respiratory syndrome CoV (MERS-CoV) NSP16 (D130A) and evaluated the effect on viral infection and pathogenesis. While the absence of 2'O-MTase activity had only a marginal impact on propagation and replication in Vero cells, dNSP16 mutant MERS-CoV demonstrated significant attenuation relative to the control both in primary human airway cell cultures and in vivo. Further examination indicated that dNSP16 mutant MERS-CoV had a type I interferon (IFN)-based attenuation and was partially restored in the absence of molecules of IFN-induced proteins with tetratricopeptide repeats. Importantly, the robust attenuation permitted the use of dNSP16 mutant MERS-CoV as a live attenuated vaccine platform protecting from a challenge with a mouse-adapted MERS-CoV strain. These studies demonstrate the importance of the conserved 2'O-MTase activity for CoV pathogenesis and highlight NSP16 as a conserved universal target for rapid live attenuated vaccine design in an expanding CoV outbreak setting. IMPORTANCE Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2'O-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2'O-MTase function across CoVs.
DOI: 10.1128/mSphere.00346-17
PubMed: 29152578
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis.</title><author><name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D" last="Menachery">Vineet D. Menachery</name><affiliation><nlm:affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mitchell, Hugh D" sort="Mitchell, Hugh D" uniqKey="Mitchell H" first="Hugh D" last="Mitchell">Hugh D. Mitchell</name><affiliation><nlm:affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Dinnon, Kenneth H" sort="Dinnon, Kenneth H" uniqKey="Dinnon K" first="Kenneth H" last="Dinnon">Kenneth H. Dinnon</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Leist, Sarah R" sort="Leist, Sarah R" uniqKey="Leist S" first="Sarah R" last="Leist">Sarah R. Leist</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Yount, Boyd L" sort="Yount, Boyd L" uniqKey="Yount B" first="Boyd L" last="Yount">Boyd L. Yount</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L" last="Graham">Rachel L. Graham</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mcanarney, Eileen T" sort="Mcanarney, Eileen T" uniqKey="Mcanarney E" first="Eileen T" last="Mcanarney">Eileen T. Mcanarney</name><affiliation><nlm:affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Stratton, Kelly G" sort="Stratton, Kelly G" uniqKey="Stratton K" first="Kelly G" last="Stratton">Kelly G. Stratton</name><affiliation><nlm:affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Cockrell, Adam S" sort="Cockrell, Adam S" uniqKey="Cockrell A" first="Adam S" last="Cockrell">Adam S. Cockrell</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Debbink, Kari" sort="Debbink, Kari" uniqKey="Debbink K" first="Kari" last="Debbink">Kari Debbink</name><affiliation><nlm:affiliation>Department of Natural Sciences, Bowie State University, Bowie, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C" last="Sims">Amy C. Sims</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Waters, Katrina M" sort="Waters, Katrina M" uniqKey="Waters K" first="Katrina M" last="Waters">Katrina M. Waters</name><affiliation><nlm:affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="????"><PubDate><MedlineDate>2017 Nov-Dec</MedlineDate></PubDate></date><idno type="RBID">pubmed:29152578</idno><idno type="pmid">29152578</idno><idno type="doi">10.1128/mSphere.00346-17</idno><idno type="wicri:Area/PubMed/Corpus">000A60</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000A60</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis.</title><author><name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D" last="Menachery">Vineet D. Menachery</name><affiliation><nlm:affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mitchell, Hugh D" sort="Mitchell, Hugh D" uniqKey="Mitchell H" first="Hugh D" last="Mitchell">Hugh D. Mitchell</name><affiliation><nlm:affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Dinnon, Kenneth H" sort="Dinnon, Kenneth H" uniqKey="Dinnon K" first="Kenneth H" last="Dinnon">Kenneth H. Dinnon</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Leist, Sarah R" sort="Leist, Sarah R" uniqKey="Leist S" first="Sarah R" last="Leist">Sarah R. Leist</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Yount, Boyd L" sort="Yount, Boyd L" uniqKey="Yount B" first="Boyd L" last="Yount">Boyd L. Yount</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Graham, Rachel L" sort="Graham, Rachel L" uniqKey="Graham R" first="Rachel L" last="Graham">Rachel L. Graham</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mcanarney, Eileen T" sort="Mcanarney, Eileen T" uniqKey="Mcanarney E" first="Eileen T" last="Mcanarney">Eileen T. Mcanarney</name><affiliation><nlm:affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Stratton, Kelly G" sort="Stratton, Kelly G" uniqKey="Stratton K" first="Kelly G" last="Stratton">Kelly G. Stratton</name><affiliation><nlm:affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Cockrell, Adam S" sort="Cockrell, Adam S" uniqKey="Cockrell A" first="Adam S" last="Cockrell">Adam S. Cockrell</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Debbink, Kari" sort="Debbink, Kari" uniqKey="Debbink K" first="Kari" last="Debbink">Kari Debbink</name><affiliation><nlm:affiliation>Department of Natural Sciences, Bowie State University, Bowie, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C" last="Sims">Amy C. Sims</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Waters, Katrina M" sort="Waters, Katrina M" uniqKey="Waters K" first="Katrina M" last="Waters">Katrina M. Waters</name><affiliation><nlm:affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name><affiliation><nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</nlm:affiliation></affiliation></author></analytic><series><title level="j">mSphere</title><idno type="ISSN">2379-5042</idno></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Coronaviruses (CoVs) encode a mixture of highly conserved and novel genes, as well as genetic elements necessary for infection and pathogenesis, raising the possibility of common targets for attenuation and therapeutic design. In this study, we focused on highly conserved nonstructural protein 16 (NSP16), a viral 2'<i>O</i>-methyltransferase (2'<i>O</i>-MTase) that encodes critical functions in immune modulation and infection. Using reverse genetics, we disrupted a key motif in the conserved KDKE motif of Middle East respiratory syndrome CoV (MERS-CoV) NSP16 (D130A) and evaluated the effect on viral infection and pathogenesis. While the absence of 2'<i>O</i>-MTase activity had only a marginal impact on propagation and replication in Vero cells, dNSP16 mutant MERS-CoV demonstrated significant attenuation relative to the control both in primary human airway cell cultures and <i>in vivo</i>. Further examination indicated that dNSP16 mutant MERS-CoV had a type I interferon (IFN)-based attenuation and was partially restored in the absence of molecules of IFN-induced proteins with tetratricopeptide repeats. Importantly, the robust attenuation permitted the use of dNSP16 mutant MERS-CoV as a live attenuated vaccine platform protecting from a challenge with a mouse-adapted MERS-CoV strain. These studies demonstrate the importance of the conserved 2'<i>O</i>-MTase activity for CoV pathogenesis and highlight NSP16 as a conserved universal target for rapid live attenuated vaccine design in an expanding CoV outbreak setting. <b>IMPORTANCE</b> Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2'<i>O</i>-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2'<i>O</i>-MTase function across CoVs.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">29152578</PMID><DateRevised><Year>2019</Year><Month>11</Month><Day>20</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Print">2379-5042</ISSN><JournalIssue CitedMedium="Print"><Volume>2</Volume><Issue>6</Issue><PubDate><MedlineDate>2017 Nov-Dec</MedlineDate></PubDate></JournalIssue><Title>mSphere</Title><ISOAbbreviation>mSphere</ISOAbbreviation></Journal><ArticleTitle>Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">e00346-17</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1128/mSphere.00346-17</ELocationID><Abstract><AbstractText>Coronaviruses (CoVs) encode a mixture of highly conserved and novel genes, as well as genetic elements necessary for infection and pathogenesis, raising the possibility of common targets for attenuation and therapeutic design. In this study, we focused on highly conserved nonstructural protein 16 (NSP16), a viral 2'<i>O</i>-methyltransferase (2'<i>O</i>-MTase) that encodes critical functions in immune modulation and infection. Using reverse genetics, we disrupted a key motif in the conserved KDKE motif of Middle East respiratory syndrome CoV (MERS-CoV) NSP16 (D130A) and evaluated the effect on viral infection and pathogenesis. While the absence of 2'<i>O</i>-MTase activity had only a marginal impact on propagation and replication in Vero cells, dNSP16 mutant MERS-CoV demonstrated significant attenuation relative to the control both in primary human airway cell cultures and <i>in vivo</i>. Further examination indicated that dNSP16 mutant MERS-CoV had a type I interferon (IFN)-based attenuation and was partially restored in the absence of molecules of IFN-induced proteins with tetratricopeptide repeats. Importantly, the robust attenuation permitted the use of dNSP16 mutant MERS-CoV as a live attenuated vaccine platform protecting from a challenge with a mouse-adapted MERS-CoV strain. These studies demonstrate the importance of the conserved 2'<i>O</i>-MTase activity for CoV pathogenesis and highlight NSP16 as a conserved universal target for rapid live attenuated vaccine design in an expanding CoV outbreak setting. <b>IMPORTANCE</b> Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2'<i>O</i>-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2'<i>O</i>-MTase function across CoVs.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Menachery</LastName><ForeName>Vineet D</ForeName><Initials>VD</Initials><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gralinski</LastName><ForeName>Lisa E</ForeName><Initials>LE</Initials><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mitchell</LastName><ForeName>Hugh D</ForeName><Initials>HD</Initials><AffiliationInfo><Affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dinnon</LastName><ForeName>Kenneth H</ForeName><Initials>KH</Initials><Suffix>3rd</Suffix><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leist</LastName><ForeName>Sarah R</ForeName><Initials>SR</Initials><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yount</LastName><ForeName>Boyd L</ForeName><Initials>BL</Initials><Suffix>Jr</Suffix><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Graham</LastName><ForeName>Rachel L</ForeName><Initials>RL</Initials><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McAnarney</LastName><ForeName>Eileen T</ForeName><Initials>ET</Initials><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stratton</LastName><ForeName>Kelly G</ForeName><Initials>KG</Initials><AffiliationInfo><Affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cockrell</LastName><ForeName>Adam S</ForeName><Initials>AS</Initials><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Debbink</LastName><ForeName>Kari</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Natural Sciences, Bowie State University, Bowie, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sims</LastName><ForeName>Amy C</ForeName><Initials>AC</Initials><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Waters</LastName><ForeName>Katrina M</ForeName><Initials>KM</Initials><AffiliationInfo><Affiliation>Pacific Northwest National Laboratory, Richland, Washington, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baric</LastName><ForeName>Ralph S</ForeName><Initials>RS</Initials><AffiliationInfo><Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R00 AG049092</GrantID><Acronym>AG</Acronym><Agency>NIA NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>F32 AI102561</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>K99 AG049092</GrantID><Acronym>AG</Acronym><Agency>NIA NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>U19 AI106772</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>U19 AI100625</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 DK065988</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>11</Month><Day>15</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>mSphere</MedlineTA><NlmUniqueID>101674533</NlmUniqueID><ISSNLinking>2379-5042</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">IFIT</Keyword><Keyword MajorTopicYN="N">MERS-CoV</Keyword><Keyword MajorTopicYN="N">SARS-CoV</Keyword><Keyword MajorTopicYN="N">coronavirus</Keyword><Keyword MajorTopicYN="N">emerging virus</Keyword><Keyword MajorTopicYN="N">live attenuated</Keyword><Keyword MajorTopicYN="N">methyltransferase</Keyword><Keyword MajorTopicYN="N">vaccine</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2017</Year><Month>08</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>10</Month><Day>26</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>11</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>11</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>11</Month><Day>21</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId 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