Influenza HA Subtypes Demonstrate Divergent Phenotypes for Cleavage Activation and pH of Fusion: Implications for Host Range and Adaptation
Identifieur interne : 000609 ( Pmc/Checkpoint ); précédent : 000608; suivant : 000610Influenza HA Subtypes Demonstrate Divergent Phenotypes for Cleavage Activation and pH of Fusion: Implications for Host Range and Adaptation
Auteurs : Summer E. Galloway [États-Unis] ; Mark L. Reed [États-Unis] ; Charles J. Russell [États-Unis] ; David A. Steinhauer [États-Unis]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2013.
Abstract
The influenza A virus (IAV) HA protein must be activated by host cells proteases in order to prime the molecule for fusion. Consequently, the availability of activating proteases and the susceptibility of HA to protease activity represents key factors in facilitating virus infection. As such, understanding the intricacies of HA cleavage by various proteases is necessary to derive insights into the emergence of pandemic viruses. To examine these properties, we generated a panel of HAs that are representative of the 16 HA subtypes that circulate in aquatic birds, as well as HAs representative of the subtypes that have infected the human population over the last century. We examined the susceptibility of the panel of HA proteins to trypsin, as well as human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2). Additionally, we examined the pH at which these HAs mediated membrane fusion, as this property is related to the stability of the HA molecule and influences the capacity of influenza viruses to remain infectious in natural environments. Our results show that cleavage efficiency can vary significantly for individual HAs, depending on the protease, and that some HA subtypes display stringent selectivity for specific proteases as activators of fusion function. Additionally, we found that the pH of fusion varies by 0.7 pH units among the subtypes, and notably, we observed that the pH of fusion for most HAs from human isolates was lower than that observed from avian isolates of the same subtype. Overall, these data provide the first broad-spectrum analysis of cleavage-activation and membrane fusion characteristics for all of the IAV HA subtypes, and also show that there are substantial differences between the subtypes that may influence transmission among hosts and establishment in new species.
Url:
DOI: 10.1371/journal.ppat.1003151
PubMed: 23459660
PubMed Central: 3573126
Affiliations:
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Galloway</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</region></placeName></affiliation></author><author><name sortKey="Reed, Mark L" sort="Reed, Mark L" uniqKey="Reed M" first="Mark L." last="Reed">Mark L. Reed</name><affiliation wicri:level="2"><nlm:aff id="aff2"><addr-line>Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Russell, Charles J" sort="Russell, Charles J" uniqKey="Russell C" first="Charles J." last="Russell">Charles J. Russell</name><affiliation wicri:level="2"><nlm:aff id="aff2"><addr-line>Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff3"><addr-line>Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Steinhauer, David A" sort="Steinhauer, David A" uniqKey="Steinhauer D" first="David A." last="Steinhauer">David A. Steinhauer</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia</wicri:regionArea><placeName><region type="state">Géorgie (États-Unis)</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="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The influenza A virus (IAV) HA protein must be activated by host cells proteases in order to prime the molecule for fusion. Consequently, the availability of activating proteases and the susceptibility of HA to protease activity represents key factors in facilitating virus infection. As such, understanding the intricacies of HA cleavage by various proteases is necessary to derive insights into the emergence of pandemic viruses. To examine these properties, we generated a panel of HAs that are representative of the 16 HA subtypes that circulate in aquatic birds, as well as HAs representative of the subtypes that have infected the human population over the last century. We examined the susceptibility of the panel of HA proteins to trypsin, as well as human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2). Additionally, we examined the pH at which these HAs mediated membrane fusion, as this property is related to the stability of the HA molecule and influences the capacity of influenza viruses to remain infectious in natural environments. Our results show that cleavage efficiency can vary significantly for individual HAs, depending on the protease, and that some HA subtypes display stringent selectivity for specific proteases as activators of fusion function. Additionally, we found that the pH of fusion varies by 0.7 pH units among the subtypes, and notably, we observed that the pH of fusion for most HAs from human isolates was lower than that observed from avian isolates of the same subtype. Overall, these data provide the first broad-spectrum analysis of cleavage-activation and membrane fusion characteristics for all of the IAV HA subtypes, and also show that there are substantial differences between the subtypes that may influence transmission among hosts and establishment in new species.</p></div></front><back><div1 type="bibliography"><listBibl><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="Tong, S" uniqKey="Tong S">S Tong</name></author><author><name sortKey="Li, Y" uniqKey="Li Y">Y Li</name></author><author><name sortKey="Rivailler, 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<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">23459660</article-id><article-id pub-id-type="pmc">3573126</article-id><article-id pub-id-type="publisher-id">PPATHOGENS-D-12-01218</article-id><article-id pub-id-type="doi">10.1371/journal.ppat.1003151</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</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Virology</subject></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Influenza HA Subtypes Demonstrate Divergent Phenotypes for Cleavage Activation and pH of Fusion: Implications for Host Range and Adaptation</article-title><alt-title alt-title-type="running-head">Phenotypic Analysis of Influenza HA Subtypes</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Galloway</surname><given-names>Summer E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Reed</surname><given-names>Mark L.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Russell</surname><given-names>Charles J.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Steinhauer</surname><given-names>David A.</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>Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Kawaoka</surname><given-names>Yoshihiro</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Wisconsin-Madison, United States of America</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>sgallo2@emory.edu</email> (SEG); <email>dsteinh@emory.edu</email> (DAS)</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: SEG DAS CJR. Performed the experiments: SEG MLR. Analyzed the data: SEG DAS. Contributed reagents/materials/analysis tools: CJR. Wrote the paper: SEG.</p></fn></author-notes><pub-date pub-type="collection"><month>2</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>14</day><month>2</month><year>2013</year></pub-date><volume>9</volume><issue>2</issue><elocation-id>e1003151</elocation-id><history><date date-type="received"><day>21</day><month>5</month><year>2012</year></date><date date-type="accepted"><day>7</day><month>12</month><year>2012</year></date></history><permissions><copyright-statement>© 2013 Galloway et al</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>Galloway et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><abstract><p>The influenza A virus (IAV) HA protein must be activated by host cells proteases in order to prime the molecule for fusion. Consequently, the availability of activating proteases and the susceptibility of HA to protease activity represents key factors in facilitating virus infection. As such, understanding the intricacies of HA cleavage by various proteases is necessary to derive insights into the emergence of pandemic viruses. To examine these properties, we generated a panel of HAs that are representative of the 16 HA subtypes that circulate in aquatic birds, as well as HAs representative of the subtypes that have infected the human population over the last century. We examined the susceptibility of the panel of HA proteins to trypsin, as well as human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2). Additionally, we examined the pH at which these HAs mediated membrane fusion, as this property is related to the stability of the HA molecule and influences the capacity of influenza viruses to remain infectious in natural environments. Our results show that cleavage efficiency can vary significantly for individual HAs, depending on the protease, and that some HA subtypes display stringent selectivity for specific proteases as activators of fusion function. Additionally, we found that the pH of fusion varies by 0.7 pH units among the subtypes, and notably, we observed that the pH of fusion for most HAs from human isolates was lower than that observed from avian isolates of the same subtype. Overall, these data provide the first broad-spectrum analysis of cleavage-activation and membrane fusion characteristics for all of the IAV HA subtypes, and also show that there are substantial differences between the subtypes that may influence transmission among hosts and establishment in new species.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>IAV is associated with significant morbidity and mortality, and represents a challenging public health threat that affects social and economic welfare each year, particularly during IAV pandemics. Although we know that all human strains derive, either directly or via intermediate hosts, from avian viral sources, we know very little about the phenotypic characteristics of the 16 HA subtypes that circulate in aquatic birds and have potential to infect mammals. HA membrane fusion properties, in conjunction with the characteristics for protease activation of HA, a requirement for fusion, are critical factors involved in the ecology and transmission of IAVs, and need to be understood if we are to derive explanations for how pandemic viruses emerge in humans. We examined the cleavage-activation and membrane fusion characteristics for the 16 HA subtypes by transiently expressing HA proteins in cells. Our findings show that the cleavability of the HAs vary considerably between subtypes and depending on the protease. Additionally, analysis of the pH of fusion for each subtype showed that HA stability varied significantly among the subtypes, as well as within subtypes from viruses isolated from different species. Overall, these data have implications for host range, potential for adaptation, and persistence in natural environments.</p></abstract><funding-group><funding-statement>This work was supported by the U.S. Department of Health and Human Services contract HHSN266200700006C (NIAID Centers of Excellence for Influenza Research and Surveillance) as well as a Ruth L. Kirschstein National Research Service Award from the NIAID (1F32AI091105) awarded to SEG. 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="17"></page-count></counts></article-meta></front></pmc><affiliations><list><country><li>États-Unis</li></country><region><li>Géorgie (États-Unis)</li><li>Tennessee</li></region></list><tree><country name="États-Unis"><region name="Géorgie (États-Unis)"><name sortKey="Galloway, Summer E" sort="Galloway, Summer E" uniqKey="Galloway S" first="Summer E." last="Galloway">Summer E. Galloway</name></region><name sortKey="Reed, Mark L" sort="Reed, Mark L" uniqKey="Reed M" first="Mark L." last="Reed">Mark L. Reed</name><name sortKey="Russell, Charles J" sort="Russell, Charles J" uniqKey="Russell C" first="Charles J." last="Russell">Charles J. Russell</name><name sortKey="Russell, Charles J" sort="Russell, Charles J" uniqKey="Russell C" first="Charles J." last="Russell">Charles J. Russell</name><name sortKey="Steinhauer, David A" sort="Steinhauer, David A" uniqKey="Steinhauer D" first="David A." last="Steinhauer">David A. Steinhauer</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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