The influenza virus hemagglutinin head evolves faster than the stalk domain
Identifieur interne : 000201 ( Pmc/Curation ); précédent : 000200; suivant : 000202The influenza virus hemagglutinin head evolves faster than the stalk domain
Auteurs : Ericka Kirkpatrick [États-Unis] ; Xueting Qiu [États-Unis] ; Patrick C. Wilson [États-Unis] ; Justin Bahl [États-Unis, Singapour] ; Florian Krammer [États-Unis]Source :
- Scientific Reports [ 2045-2322 ] ; 2018.
Abstract
The limited ability of current influenza virus vaccines to protect from antigenically drifted or shifted viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current influenza virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the hemagglutinin, the major surface glycoprotein of the virus, the hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between influenza A virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing. Here, we performed an evolutionary analysis of the stalk domains of the hemagglutinin of pre-pandemic seasonal H1N1, pandemic H1N1, seasonal H3N2, and influenza B viruses and show quantitatively for the first time that the stalk domain is evolving at a rate that is significantly slower than that of the head domain. Additionally, we found that the cross-reactive epitopes in the stalk domain targeted by broadly neutralizing monoclonal antibodies are evolving at an even slower rate compared to the full head and stalk regions of the protein. Finally, a fixed-effects likelihood selection analysis was performed for these virus groups in both the head and stalk domains. While several positive selection sites were found in the head domain, only a single site in the stalk domain of pre-pandemic seasonal H1 hemagglutinin was identified at amino acid position 468 (H1 numbering from methionine). This site is not located in or close to the epitopes of cross-reactive anti-stalk monoclonal antibodies. Furthermore, we found that changes in this site do not significantly impact virus binding or neutralization by human anti-stalk antibodies, suggesting that some positive selection in the stalk domain is independent of immune pressures. We conclude that, while the stalk domain does evolve over time, this evolution is slow and, historically, is not directed to aid in evading neutralizing antibody responses.
Url:
DOI: 10.1038/s41598-018-28706-1
PubMed: 29992986
PubMed Central: 6041311
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<front><div type="abstract" xml:lang="en"><p id="Par1">The limited ability of current influenza virus vaccines to protect from antigenically drifted or shifted viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current influenza virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the hemagglutinin, the major surface glycoprotein of the virus, the hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between influenza A virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing. Here, we performed an evolutionary analysis of the stalk domains of the hemagglutinin of pre-pandemic seasonal H1N1, pandemic H1N1, seasonal H3N2, and influenza B viruses and show quantitatively for the first time that the stalk domain is evolving at a rate that is significantly slower than that of the head domain. Additionally, we found that the cross-reactive epitopes in the stalk domain targeted by broadly neutralizing monoclonal antibodies are evolving at an even slower rate compared to the full head and stalk regions of the protein. Finally, a fixed-effects likelihood selection analysis was performed for these virus groups in both the head and stalk domains. While several positive selection sites were found in the head domain, only a single site in the stalk domain of pre-pandemic seasonal H1 hemagglutinin was identified at amino acid position 468 (H1 numbering from methionine). This site is not located in or close to the epitopes of cross-reactive anti-stalk monoclonal antibodies. Furthermore, we found that changes in this site do not significantly impact virus binding or neutralization by human anti-stalk antibodies, suggesting that some positive selection in the stalk domain is independent of immune pressures. We conclude that, while the stalk domain does evolve over time, this evolution is slow and, historically, is not directed to aid in evading neutralizing antibody responses.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id>
<journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id>
<journal-title-group><journal-title>Scientific Reports</journal-title>
</journal-title-group>
<issn pub-type="epub">2045-2322</issn>
<publisher><publisher-name>Nature Publishing Group UK</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">29992986</article-id>
<article-id pub-id-type="pmc">6041311</article-id>
<article-id pub-id-type="publisher-id">28706</article-id>
<article-id pub-id-type="doi">10.1038/s41598-018-28706-1</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>The influenza virus hemagglutinin head evolves faster than the stalk domain</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kirkpatrick</surname>
<given-names>Ericka</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Qiu</surname>
<given-names>Xueting</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wilson</surname>
<given-names>Patrick C.</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-7572-4300</contrib-id>
<name><surname>Bahl</surname>
<given-names>Justin</given-names>
</name>
<address><email>justin.bahl@uth.tmc.edu</email>
</address>
<xref ref-type="aff" rid="Aff3">3</xref>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4121-776X</contrib-id>
<name><surname>Krammer</surname>
<given-names>Florian</given-names>
</name>
<address><email>florian.krammer@mssm.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0670 2351</institution-id>
<institution-id institution-id-type="GRID">grid.59734.3c</institution-id>
<institution>Department of Microbiology,</institution>
<institution>Icahn School of Medicine at Mount Sinai,</institution>
</institution-wrap>
New York, NY USA</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0670 2351</institution-id>
<institution-id institution-id-type="GRID">grid.59734.3c</institution-id>
<institution>Graduate School of Biomedical Sciences,</institution>
<institution>Icahn School of Medicine at Mount Sinai,</institution>
</institution-wrap>
New York, NY USA</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9206 2401</institution-id>
<institution-id institution-id-type="GRID">grid.267308.8</institution-id>
<institution>University of Texas School of Public Health,</institution>
</institution-wrap>
Houston, TX USA</aff>
<aff id="Aff4"><label>4</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 7822</institution-id>
<institution-id institution-id-type="GRID">grid.170205.1</institution-id>
<institution>Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research,</institution>
<institution>University of Chicago,</institution>
</institution-wrap>
Chicago, IL USA</aff>
<aff id="Aff5"><label>5</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0385 0924</institution-id>
<institution-id institution-id-type="GRID">grid.428397.3</institution-id>
<institution>Program in Emerging Infectious Diseases,</institution>
<institution>Duke-National University of Singapore Graduate Medical School,</institution>
</institution-wrap>
Singapore, Singapore</aff>
</contrib-group>
<pub-date pub-type="epub"><day>11</day>
<month>7</month>
<year>2018</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>11</day>
<month>7</month>
<year>2018</year>
</pub-date>
<pub-date pub-type="collection"><year>2018</year>
</pub-date>
<volume>8</volume>
<elocation-id>10432</elocation-id>
<history><date date-type="received"><day>18</day>
<month>4</month>
<year>2018</year>
</date>
<date date-type="accepted"><day>28</day>
<month>6</month>
<year>2018</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2018</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
.</license-p>
</license>
</permissions>
<abstract id="Abs1"><p id="Par1">The limited ability of current influenza virus vaccines to protect from antigenically drifted or shifted viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current influenza virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the hemagglutinin, the major surface glycoprotein of the virus, the hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between influenza A virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing. Here, we performed an evolutionary analysis of the stalk domains of the hemagglutinin of pre-pandemic seasonal H1N1, pandemic H1N1, seasonal H3N2, and influenza B viruses and show quantitatively for the first time that the stalk domain is evolving at a rate that is significantly slower than that of the head domain. Additionally, we found that the cross-reactive epitopes in the stalk domain targeted by broadly neutralizing monoclonal antibodies are evolving at an even slower rate compared to the full head and stalk regions of the protein. Finally, a fixed-effects likelihood selection analysis was performed for these virus groups in both the head and stalk domains. While several positive selection sites were found in the head domain, only a single site in the stalk domain of pre-pandemic seasonal H1 hemagglutinin was identified at amino acid position 468 (H1 numbering from methionine). This site is not located in or close to the epitopes of cross-reactive anti-stalk monoclonal antibodies. Furthermore, we found that changes in this site do not significantly impact virus binding or neutralization by human anti-stalk antibodies, suggesting that some positive selection in the stalk domain is independent of immune pressures. We conclude that, while the stalk domain does evolve over time, this evolution is slow and, historically, is not directed to aid in evading neutralizing antibody responses.</p>
</abstract>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000060</institution-id>
<institution>U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution>
</institution-wrap>
</funding-source>
<award-id>U19AI109946</award-id>
<award-id>HHSN272201400005C</award-id>
<award-id>HHSN272201400006C</award-id>
<award-id>HHSN272201400008C</award-id>
<principal-award-recipient><name><surname>Wilson</surname>
<given-names>Patrick C.</given-names>
</name>
<name><surname>Bahl</surname>
<given-names>Justin</given-names>
</name>
<name><surname>Krammer</surname>
<given-names>Florian</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2018</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>
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