Influenza Hemagglutinin (HA) Stem Region Mutations That Stabilize or Destabilize the Structure of Multiple HA Subtypes
Identifieur interne : 000020 ( Pmc/Curation ); précédent : 000019; suivant : 000021Influenza Hemagglutinin (HA) Stem Region Mutations That Stabilize or Destabilize the Structure of Multiple HA Subtypes
Auteurs : Lauren Byrd-Leotis ; Summer E. Galloway ; Evangeline Agbogu ; David A. SteinhauerSource :
- Journal of Virology [ 0022-538X ] ; 2015.
Abstract
Influenza A viruses enter host cells through endosomes, where acidification induces irreversible conformational changes of the viral hemagglutinin (HA) that drive the membrane fusion process. The prefusion conformation of the HA is metastable, and the pH of fusion can vary significantly among HA strains and subtypes. Furthermore, an accumulating body of evidence implicates HA stability properties as partial determinants of influenza host range, transmission phenotype, and pathogenic potential. Although previous studies have identified HA mutations that can affect HA stability, these have been limited to a small selection of HA strains and subtypes. Here we report a mutational analysis of HA stability utilizing a panel of expressed HAs representing a broad range of HA subtypes and strains, including avian representatives across the phylogenetic spectrum and several human strains. We focused on two highly conserved residues in the HA stem region: HA2 position 58, located at the membrane distal tip of the short helix of the hairpin loop structure, and HA2 position 112, located in the long helix in proximity to the fusion peptide. We demonstrate that a K58I mutation confers an acid-stable phenotype for nearly all HAs examined, whereas a D112G mutation consistently leads to elevated fusion pH. The results enhance our understanding of HA stability across multiple subtypes and provide an additional tool for risk assessment for circulating strains that may have other hallmarks of human adaptation. Furthermore, the K58I mutants, in particular, may be of interest for potential use in the development of vaccines with improved stability profiles.
Url:
DOI: 10.1128/JVI.00057-15
PubMed: 25653452
PubMed Central: 4442347
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<author><name sortKey="Galloway, Summer E" sort="Galloway, Summer E" uniqKey="Galloway S" first="Summer E." last="Galloway">Summer E. Galloway</name>
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<author><name sortKey="Agbogu, Evangeline" sort="Agbogu, Evangeline" uniqKey="Agbogu E" first="Evangeline" last="Agbogu">Evangeline Agbogu</name>
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<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Influenza A viruses enter host cells through endosomes, where acidification induces irreversible conformational changes of the viral hemagglutinin (HA) that drive the membrane fusion process. The prefusion conformation of the HA is metastable, and the pH of fusion can vary significantly among HA strains and subtypes. Furthermore, an accumulating body of evidence implicates HA stability properties as partial determinants of influenza host range, transmission phenotype, and pathogenic potential. Although previous studies have identified HA mutations that can affect HA stability, these have been limited to a small selection of HA strains and subtypes. Here we report a mutational analysis of HA stability utilizing a panel of expressed HAs representing a broad range of HA subtypes and strains, including avian representatives across the phylogenetic spectrum and several human strains. We focused on two highly conserved residues in the HA stem region: HA2 position 58, located at the membrane distal tip of the short helix of the hairpin loop structure, and HA2 position 112, located in the long helix in proximity to the fusion peptide. We demonstrate that a K58I mutation confers an acid-stable phenotype for nearly all HAs examined, whereas a D112G mutation consistently leads to elevated fusion pH. The results enhance our understanding of HA stability across multiple subtypes and provide an additional tool for risk assessment for circulating strains that may have other hallmarks of human adaptation. Furthermore, the K58I mutants, in particular, may be of interest for potential use in the development of vaccines with improved stability profiles.</p>
<p><bold>IMPORTANCE</bold>
The influenza A hemagglutinin glycoprotein (HA) mediates the receptor binding and membrane fusion functions that are essential for virus entry into host cells. While receptor binding has long been recognized for its role in host species specificity and transmission, membrane fusion and associated properties of HA stability have only recently been appreciated as potential determinants. We show here that mutations can be introduced at highly conserved positions to stabilize or destabilize the HA structure of multiple HA subtypes, expanding our knowledge base for this important phenotype. The practical implications of these findings extend to the field of vaccine design, since the HA mutations characterized here could potentially be utilized across a broad spectrum of influenza virus subtypes to improve the stability of vaccine strains or components.</p>
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<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>
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<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>
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<article-meta><article-id pub-id-type="pmid">25653452</article-id>
<article-id pub-id-type="pmc">4442347</article-id>
<article-id pub-id-type="publisher-id">00057-15</article-id>
<article-id pub-id-type="doi">10.1128/JVI.00057-15</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Structure and Assembly</subject>
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</article-categories>
<title-group><article-title>Influenza Hemagglutinin (HA) Stem Region Mutations That Stabilize or Destabilize the Structure of Multiple HA Subtypes</article-title>
<alt-title alt-title-type="running-head">Stabilizing and Destabilizing Influenza HA2 Mutations</alt-title>
<alt-title alt-title-type="short-authors">Byrd-Leotis et al.</alt-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Byrd-Leotis</surname>
<given-names>Lauren</given-names>
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<contrib contrib-type="author"><name><surname>Galloway</surname>
<given-names>Summer E.</given-names>
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<xref ref-type="author-notes" rid="fn1">*</xref>
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<contrib contrib-type="author"><name><surname>Agbogu</surname>
<given-names>Evangeline</given-names>
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<contrib contrib-type="author" corresp="yes"><name><surname>Steinhauer</surname>
<given-names>David A.</given-names>
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</contrib>
<aff>Department of Microbiology and Immunology, Rollins Research Center, Emory University School of Medicine, Atlanta, Georgia, USA</aff>
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<contrib-group><contrib contrib-type="editor"><name><surname>García-Sastre</surname>
<given-names>A.</given-names>
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<role>Editor</role>
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<author-notes><corresp id="cor1">Address correspondence to David A. Steinhauer, <email>dsteinh@emory.edu</email>
.</corresp>
<fn id="fn1" fn-type="present-address"><label>*</label>
<p>Present address: Summer E. Galloway, AAAS Science and Technology Fellow, U.S. Department of Defense, Washington, DC, USA.</p>
</fn>
<fn fn-type="other"><p><bold>Citation</bold>
Byrd-Leotis L, Galloway SE, Agbogu E, Steinhauer DA. 2015. Influenza hemagglutinin (HA) stem region mutations that stabilize or destabilize the structure of multiple HA subtypes. J Virol 89:4504–4516. doi:<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1128/JVI.00057-15">10.1128/JVI.00057-15</ext-link>
.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>4</day>
<month>2</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><day>15</day>
<month>4</month>
<year>2015</year>
</pub-date>
<volume>89</volume>
<issue>8</issue>
<fpage>4504</fpage>
<lpage>4516</lpage>
<history><date date-type="received"><day>8</day>
<month>1</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>2</day>
<month>2</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>American Society for Microbiology</copyright-holder>
</permissions>
<self-uri content-type="pdf" xlink:href="zjv00815004504.pdf"></self-uri>
<abstract><title>ABSTRACT</title>
<p>Influenza A viruses enter host cells through endosomes, where acidification induces irreversible conformational changes of the viral hemagglutinin (HA) that drive the membrane fusion process. The prefusion conformation of the HA is metastable, and the pH of fusion can vary significantly among HA strains and subtypes. Furthermore, an accumulating body of evidence implicates HA stability properties as partial determinants of influenza host range, transmission phenotype, and pathogenic potential. Although previous studies have identified HA mutations that can affect HA stability, these have been limited to a small selection of HA strains and subtypes. Here we report a mutational analysis of HA stability utilizing a panel of expressed HAs representing a broad range of HA subtypes and strains, including avian representatives across the phylogenetic spectrum and several human strains. We focused on two highly conserved residues in the HA stem region: HA2 position 58, located at the membrane distal tip of the short helix of the hairpin loop structure, and HA2 position 112, located in the long helix in proximity to the fusion peptide. We demonstrate that a K58I mutation confers an acid-stable phenotype for nearly all HAs examined, whereas a D112G mutation consistently leads to elevated fusion pH. The results enhance our understanding of HA stability across multiple subtypes and provide an additional tool for risk assessment for circulating strains that may have other hallmarks of human adaptation. Furthermore, the K58I mutants, in particular, may be of interest for potential use in the development of vaccines with improved stability profiles.</p>
<p><bold>IMPORTANCE</bold>
The influenza A hemagglutinin glycoprotein (HA) mediates the receptor binding and membrane fusion functions that are essential for virus entry into host cells. While receptor binding has long been recognized for its role in host species specificity and transmission, membrane fusion and associated properties of HA stability have only recently been appreciated as potential determinants. We show here that mutations can be introduced at highly conserved positions to stabilize or destabilize the HA structure of multiple HA subtypes, expanding our knowledge base for this important phenotype. The practical implications of these findings extend to the field of vaccine design, since the HA mutations characterized here could potentially be utilized across a broad spectrum of influenza virus subtypes to improve the stability of vaccine strains or components.</p>
</abstract>
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