A Dual Motif in the Hemagglutinin of H5N1 Goose/Guangdong-Like Highly Pathogenic Avian Influenza Virus Strains Is Conserved from Their Early Evolution and Increases both Membrane Fusion pH and Virulence
Identifieur interne : 000E84 ( Ncbi/Merge ); précédent : 000E83; suivant : 000E85A Dual Motif in the Hemagglutinin of H5N1 Goose/Guangdong-Like Highly Pathogenic Avian Influenza Virus Strains Is Conserved from Their Early Evolution and Increases both Membrane Fusion pH and Virulence
Auteurs : Ute Wessels [Allemagne] ; Elsayed M. Abdelwhab [Allemagne] ; Jutta Veits [Allemagne] ; Donata Hoffmann [Allemagne] ; Svenja Mamerow [Allemagne] ; Olga Stech [Allemagne] ; Jan Hellert [France] ; Martin Beer [Allemagne] ; Thomas C. Mettenleiter [Allemagne] ; Jürgen Stech [Allemagne]Source :
- Journal of Virology [ 0022-538X ] ; 2018.
Abstract
Zoonotic highly pathogenic avian influenza viruses (HPAIV) have raised serious public health concerns of a novel pandemic. Their prime virulence determinant is the polybasic hemagglutinin (HA) cleavage site. However, required coadaptations in the HA (and other genes) remained uncertain. Here, we identified the dual motif 123R/124I in the HA head that increases the activation pH of HA-mediated membrane fusion, essential for virus genome release into the cytoplasm. This motif is extremely predominant in H5 HPAIV and emerged already in the earliest 1997 H5N1 HPAIV. Reversion to 123S or 124T, characteristic of low-pathogenic strains, attenuated the virus in chicken and mice, accompanied by a decreased HA activation pH. This increased pH sensitivity of H5 HPAIV extends the viral tropism to cells with less-acidic endosomes, e.g., within the respiratory tract. Therefore, early HA adaptation to increased acid sensitivity promoted the emergence of H5 Goose/Guangdong-like HPAIV strains and is required for their zoonotic potential.
Url:
DOI: 10.1128/JVI.00778-18
PubMed: 29899102
PubMed Central: 6096801
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Abdelwhab</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems</wicri:regionArea><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion></affiliation></author><author><name sortKey="Veits, Jutta" sort="Veits, Jutta" uniqKey="Veits J" first="Jutta" last="Veits">Jutta Veits</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems</wicri:regionArea><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion></affiliation></author><author><name sortKey="Hoffmann, Donata" sort="Hoffmann, Donata" uniqKey="Hoffmann D" first="Donata" last="Hoffmann">Donata Hoffmann</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institute of Diagnostic Virology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Diagnostic Virology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems</wicri:regionArea><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion></affiliation></author><author><name sortKey="Mamerow, Svenja" sort="Mamerow, Svenja" uniqKey="Mamerow S" first="Svenja" last="Mamerow">Svenja Mamerow</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems</wicri:regionArea><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion></affiliation></author><author><name sortKey="Stech, Olga" sort="Stech, Olga" uniqKey="Stech O" first="Olga" last="Stech">Olga Stech</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems</wicri:regionArea><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion></affiliation></author><author><name sortKey="Hellert, Jan" sort="Hellert, Jan" uniqKey="Hellert J" first="Jan" last="Hellert">Jan Hellert</name><affiliation wicri:level="3"><nlm:aff id="aff3">Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Beer, Martin" sort="Beer, Martin" uniqKey="Beer M" first="Martin" last="Beer">Martin Beer</name><affiliation wicri:level="1"><nlm:aff id="aff2">Institute of Diagnostic Virology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Diagnostic Virology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems</wicri:regionArea><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion></affiliation></author><author><name sortKey="Mettenleiter, Thomas C" sort="Mettenleiter, Thomas C" uniqKey="Mettenleiter T" first="Thomas C." last="Mettenleiter">Thomas C. Mettenleiter</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems</wicri:regionArea><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion></affiliation></author><author><name sortKey="Stech, Jurgen" sort="Stech, Jurgen" uniqKey="Stech J" first="Jürgen" last="Stech">Jürgen Stech</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems</wicri:regionArea><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion><wicri:noRegion>Greifswald-Insel Riems</wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Zoonotic highly pathogenic avian influenza viruses (HPAIV) have raised serious public health concerns of a novel pandemic. Their prime virulence determinant is the polybasic hemagglutinin (HA) cleavage site. However, required coadaptations in the HA (and other genes) remained uncertain. Here, we identified the dual motif 123R/124I in the HA head that increases the activation pH of HA-mediated membrane fusion, essential for virus genome release into the cytoplasm. This motif is extremely predominant in H5 HPAIV and emerged already in the earliest 1997 H5N1 HPAIV. Reversion to 123S or 124T, characteristic of low-pathogenic strains, attenuated the virus in chicken and mice, accompanied by a decreased HA activation pH. This increased pH sensitivity of H5 HPAIV extends the viral tropism to cells with less-acidic endosomes, e.g., within the respiratory tract. Therefore, early HA adaptation to increased acid sensitivity promoted the emergence of H5 Goose/Guangdong-like HPAIV strains and is required for their zoonotic potential.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id><journal-id journal-id-type="iso-abbrev">J. Virol</journal-id><journal-id journal-id-type="hwp">jvi</journal-id><journal-id journal-id-type="pmc">jvi</journal-id><journal-id journal-id-type="publisher-id">JVI</journal-id><journal-title-group><journal-title>Journal of Virology</journal-title></journal-title-group><issn pub-type="ppub">0022-538X</issn><issn pub-type="epub">1098-5514</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29899102</article-id><article-id pub-id-type="pmc">6096801</article-id><article-id pub-id-type="publisher-id">00778-18</article-id><article-id pub-id-type="doi">10.1128/JVI.00778-18</article-id><article-categories><subj-group subj-group-type="heading"><subject>Pathogenesis and Immunity</subject></subj-group></article-categories><title-group><article-title>A Dual Motif in the Hemagglutinin of H5N1 Goose/Guangdong-Like Highly Pathogenic Avian Influenza Virus Strains Is Conserved from Their Early Evolution and Increases both Membrane Fusion pH and Virulence</article-title><alt-title alt-title-type="running-head">Dual HA Motif Crucial for H5N1 HPAIV Evolution</alt-title><alt-title alt-title-type="short-authors">Wessels et al.</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wessels</surname><given-names>Ute</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Abdelwhab</surname><given-names>Elsayed M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Veits</surname><given-names>Jutta</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hoffmann</surname><given-names>Donata</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mamerow</surname><given-names>Svenja</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stech</surname><given-names>Olga</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hellert</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Beer</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mettenleiter</surname><given-names>Thomas C.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-3187-702X</contrib-id><name><surname>Stech</surname><given-names>Jürgen</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><aff id="aff1"><label>a</label>Institute of Molecular Virology and Cell Biology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</aff><aff id="aff2"><label>b</label>Institute of Diagnostic Virology, Friedrich Loeffler Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany</aff><aff id="aff3"><label>c</label>Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, Paris, France</aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Schultz-Cherry</surname><given-names>Stacey</given-names></name><role>Editor</role><aff>St. Jude Children's Research Hospital</aff></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Jürgen Stech, <email>juergen.stech@fli.de</email>.</corresp><fn fn-type="other"><p><bold>Citation</bold> Wessels U, Abdelwhab EM, Veits J, Hoffmann D, Mamerow S, Stech O, Hellert J, Beer M, Mettenleiter TC, Stech J. 2018. A dual motif in the hemagglutinin of H5N1 Goose/Guangdong-like highly pathogenic avian influenza virus strains is conserved from their early evolution and increases both membrane fusion pH and virulence. J Virol 92:e00778-18. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.00778-18">https://doi.org/10.1128/JVI.00778-18</ext-link>.</p></fn></author-notes><pub-date pub-type="epreprint"><day>13</day><month>6</month><year>2018</year></pub-date><pub-date pub-type="epub"><day>16</day><month>8</month><year>2018</year></pub-date><pub-date pub-type="collection"><day>1</day><month>9</month><year>2018</year></pub-date><volume>92</volume><issue>17</issue><elocation-id>e00778-18</elocation-id><history><date date-type="received"><day>8</day><month>5</month><year>2018</year></date><date date-type="accepted"><day>2</day><month>6</month><year>2018</year></date></history><permissions><copyright-statement>Copyright © 2018 American Society for Microbiology.</copyright-statement><copyright-year>2018</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder><license license-type="asm" xlink:href="https://doi.org/10.1128/ASMCopyrightv2"><license-p><ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/ASMCopyrightv2">All Rights Reserved</ext-link>.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="zjv017183797001.pdf"></self-uri><abstract abstract-type="precis"><p>Zoonotic highly pathogenic avian influenza viruses (HPAIV) have raised serious public health concerns of a novel pandemic. Their prime virulence determinant is the polybasic hemagglutinin (HA) cleavage site. However, required coadaptations in the HA (and other genes) remained uncertain. Here, we identified the dual motif 123R/124I in the HA head that increases the activation pH of HA-mediated membrane fusion, essential for virus genome release into the cytoplasm. This motif is extremely predominant in H5 HPAIV and emerged already in the earliest 1997 H5N1 HPAIV. Reversion to 123S or 124T, characteristic of low-pathogenic strains, attenuated the virus in chicken and mice, accompanied by a decreased HA activation pH. This increased pH sensitivity of H5 HPAIV extends the viral tropism to cells with less-acidic endosomes, e.g., within the respiratory tract. Therefore, early HA adaptation to increased acid sensitivity promoted the emergence of H5 Goose/Guangdong-like HPAIV strains and is required for their zoonotic potential.</p></abstract><abstract><title>ABSTRACT</title><p>Zoonotic highly pathogenic avian influenza viruses (HPAIV) have raised serious public health concerns of a novel pandemic. These strains emerge from low-pathogenic precursors by the acquisition of a polybasic hemagglutinin (HA) cleavage site, the prime virulence determinant. However, required coadaptations of the HA early in HPAIV evolution remained uncertain. To address this question, we generated several HA1/HA2 chimeras and point mutants of an H5N1 clade 2.2.2 HPAIV and an H5N1 low-pathogenic strain. Initial surveys of 3,385 HPAIV H5 HA sequences revealed frequencies of 0.5% for the single amino acids 123R and 124I but a frequency of 97.5% for the dual combination. This highly conserved dual motif is still retained in contemporary H5 HPAIV, including the novel H5NX reassortants carrying neuraminidases of different subtypes, like the H5N8 and the zoonotic H5N6 strains. Remarkably, the earliest Asian H5N1 HPAIV, the Goose/Guangdong strains from 1996/1997, carried 123R only, whereas 124I appeared later in 1997. Experimental reversion in the HPAIV HA to the two residues 123S and124T, characteristic of low-pathogenic strains, prevented virus rescue, while the single substitutions attenuated the virus in both chicken and mice considerably, accompanied by a decreased HA fusion pH. This increased pH sensitivity of H5 HPAIV enables HA-mediated membrane fusion at a higher endosomal pH. Therefore, this HA adaptation may permit infection of cells with less-acidic endosomes, e.g., within the respiratory tract, resulting in an extended organ tropism. Taken together, HA coadaptation to increased acid sensitivity promoted the early evolution of H5 Goose/Guangdong-like HPAIV strains and is still required for their zoonotic potential.</p><p><bold>IMPORTANCE</bold> Zoonotic highly pathogenic avian influenza viruses (HPAIV) have raised serious public health concerns of a novel pandemic. Their prime virulence determinant is the polybasic hemagglutinin (HA) cleavage site. However, required coadaptations in the HA (and other genes) remained uncertain. Here, we identified the dual motif 123R/124I in the HA head that increases the activation pH of HA-mediated membrane fusion, essential for virus genome release into the cytoplasm. This motif is extremely predominant in H5 HPAIV and emerged already in the earliest 1997 H5N1 HPAIV. Reversion to 123S or 124T, characteristic of low-pathogenic strains, attenuated the virus in chicken and mice, accompanied by a decreased HA activation pH. This increased pH sensitivity of H5 HPAIV extends the viral tropism to cells with less-acidic endosomes, e.g., within the respiratory tract. Therefore, early HA adaptation to increased acid sensitivity promoted the emergence of H5 Goose/Guangdong-like HPAIV strains and is required for their zoonotic potential.</p></abstract><kwd-group><title>KEYWORDS</title><kwd>influenza virus</kwd><kwd>H5N1</kwd><kwd>virus evolution</kwd><kwd>HPAIV</kwd><kwd>hemagglutinin</kwd><kwd>HA</kwd></kwd-group><funding-group><award-group id="award1"><funding-source id="gs1"><institution-wrap><institution>Deutsche Forschungsgemeinschaft (DFG)</institution><institution-id>https://doi.org/10.13039/501100001659</institution-id></institution-wrap></funding-source><award-id rid="gs1">STE 1957/1-1</award-id><principal-award-recipient><name><surname>Stech</surname><given-names>Jürgen</given-names></name></principal-award-recipient></award-group></funding-group><counts><fig-count count="8"></fig-count><table-count count="5"></table-count><equation-count count="0"></equation-count><ref-count count="87"></ref-count><page-count count="19"></page-count><word-count count="10726"></word-count></counts><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>September 2018</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>Allemagne</li><li>France</li></country><region><li>Île-de-France</li></region><settlement><li>Paris</li></settlement></list><tree><country name="Allemagne"><noRegion><name sortKey="Wessels, Ute" sort="Wessels, Ute" uniqKey="Wessels U" first="Ute" last="Wessels">Ute Wessels</name></noRegion><name sortKey="Abdelwhab, Elsayed M" sort="Abdelwhab, Elsayed M" uniqKey="Abdelwhab E" first="Elsayed M." last="Abdelwhab">Elsayed M. Abdelwhab</name><name sortKey="Beer, Martin" sort="Beer, Martin" uniqKey="Beer M" first="Martin" last="Beer">Martin Beer</name><name sortKey="Hoffmann, Donata" sort="Hoffmann, Donata" uniqKey="Hoffmann D" first="Donata" last="Hoffmann">Donata Hoffmann</name><name sortKey="Mamerow, Svenja" sort="Mamerow, Svenja" uniqKey="Mamerow S" first="Svenja" last="Mamerow">Svenja Mamerow</name><name sortKey="Mettenleiter, Thomas C" sort="Mettenleiter, Thomas C" uniqKey="Mettenleiter T" first="Thomas C." last="Mettenleiter">Thomas C. Mettenleiter</name><name sortKey="Stech, Jurgen" sort="Stech, Jurgen" uniqKey="Stech J" first="Jürgen" last="Stech">Jürgen Stech</name><name sortKey="Stech, Olga" sort="Stech, Olga" uniqKey="Stech O" first="Olga" last="Stech">Olga Stech</name><name sortKey="Veits, Jutta" sort="Veits, Jutta" uniqKey="Veits J" first="Jutta" last="Veits">Jutta Veits</name></country><country name="France"><region name="Île-de-France"><name sortKey="Hellert, Jan" sort="Hellert, Jan" uniqKey="Hellert J" first="Jan" last="Hellert">Jan Hellert</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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