Complete-Proteome Mapping of Human Influenza A Adaptive Mutations: Implications for Human Transmissibility of Zoonotic Strains
Identifieur interne : 000959 ( Pmc/Checkpoint ); précédent : 000958; suivant : 000960Complete-Proteome Mapping of Human Influenza A Adaptive Mutations: Implications for Human Transmissibility of Zoonotic Strains
Auteurs : Olivo Miotto [Royaume-Uni, Thaïlande] ; A. T. Heiny [Singapour] ; Randy Albrecht [États-Unis] ; Adolfo García-Sastre [États-Unis] ; Tin Wee Tan [Singapour] ; J. Thomas August [États-Unis] ; Vladimir Brusic [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2010.
Abstract
There is widespread concern that H5N1 avian influenza A viruses will emerge as a pandemic threat, if they become capable of human-to-human (H2H) transmission. Avian strains lack this capability, which suggests that it requires important adaptive mutations. We performed a large-scale comparative analysis of proteins from avian and human strains, to produce a catalogue of mutations associated with H2H transmissibility, and to detect their presence in avian isolates.
We constructed a dataset of influenza A protein sequences from 92,343 public
database records. Human and avian sequence subsets were compared, using a
method based on
Human host adaptation appears to be complex and systemic, involving nearly all influenza proteins. Adaptation signatures suggest that the ability of H5N1 strains to infect humans is related to the presence of an unusually high number of adaptive mutations. However, these mutations appear unstable, suggesting low pandemic potential of H5N1 in its current form. In addition, adaptation signatures indicate that pandemic H1N1/09 strain possesses multiple human-transmissibility mutations, though not an unusually high number with respect to swine strains that infected humans in the past. Adaptation signatures provide a novel tool for identifying zoonotic strains with the potential to infect humans.
Url:
DOI: 10.1371/journal.pone.0009025
PubMed: 20140252
PubMed Central: 2815782
Affiliations:
- Royaume-Uni, Singapour, Thaïlande, États-Unis
- Angleterre, Maryland, Massachusetts, Oxfordshire, État de New York
- Oxford
- Université d'Oxford, Université nationale de Singapour
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PMC:2815782Le document en format XML
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<author><name sortKey="Garcia Sastre, Adolfo" sort="Garcia Sastre, Adolfo" uniqKey="Garcia Sastre A" first="Adolfo" last="García-Sastre">Adolfo García-Sastre</name>
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<author><name sortKey="August, J Thomas" sort="August, J Thomas" uniqKey="August J" first="J. Thomas" last="August">J. Thomas August</name>
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<author><name sortKey="Brusic, Vladimir" sort="Brusic, Vladimir" uniqKey="Brusic V" first="Vladimir" last="Brusic">Vladimir Brusic</name>
<affiliation wicri:level="2"><nlm:aff id="aff8"><addr-line>Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>There is widespread concern that H5N1 avian influenza A viruses will emerge
as a pandemic threat, if they become capable of human-to-human (H2H)
transmission. Avian strains lack this capability, which suggests that it
requires important adaptive mutations. We performed a large-scale
comparative analysis of proteins from avian and human strains, to produce a
catalogue of mutations associated with H2H transmissibility, and to detect
their presence in avian isolates.</p>
</sec>
<sec><title>Methodology/Principal Findings</title>
<p>We constructed a dataset of influenza A protein sequences from 92,343 public
database records. Human and avian sequence subsets were compared, using a
method based on <italic>mutual information</italic>
, to identify
<italic>characteristic sites</italic>
where human isolates present
conserved mutations. The resulting catalogue comprises 68 characteristic
sites in eight internal proteins. Subtype variability prevented the
identification of adaptive mutations in the hemagglutinin and neuraminidase
proteins. The high number of sites in the ribonucleoprotein complex suggests
interdependence between mutations in multiple proteins. Characteristic sites
are often clustered within known functional regions, suggesting their
functional roles in cellular processes. By isolating and concatenating
characteristic site residues, we defined <italic>adaptation
signatures</italic>
, which summarize the adaptive potential of specific
isolates. Most adaptive mutations emerged within three decades after the
1918 pandemic, and have remained remarkably stable thereafter. Two lineages
with stable internal protein constellations have circulated among humans
without reassorting. On the contrary, H5N1 avian and swine viruses reassort
frequently, causing both gains and losses of adaptive mutations.</p>
</sec>
<sec><title>Conclusions</title>
<p>Human host adaptation appears to be complex and systemic, involving nearly
all influenza proteins. Adaptation signatures suggest that the ability of
H5N1 strains to infect humans is related to the presence of an unusually
high number of adaptive mutations. However, these mutations appear unstable,
suggesting low pandemic potential of H5N1 in its current form. In addition,
adaptation signatures indicate that pandemic H1N1/09 strain possesses
multiple human-transmissibility mutations, though not an unusually high
number with respect to swine strains that infected humans in the past.
Adaptation signatures provide a novel tool for identifying zoonotic strains
with the potential to infect humans.</p>
</sec>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
<journal-title-group><journal-title>PLoS ONE</journal-title>
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<issn pub-type="epub">1932-6203</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
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<article-meta><article-id pub-id-type="pmid">20140252</article-id>
<article-id pub-id-type="pmc">2815782</article-id>
<article-id pub-id-type="publisher-id">09-PONE-RA-13598R1</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0009025</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline"><subject>Computational Biology</subject>
<subject>Genetics and Genomics</subject>
<subject>Infectious Diseases</subject>
<subject>Biochemistry/Bioinformatics</subject>
<subject>Computational Biology/Comparative Sequence Analysis</subject>
<subject>Computational Biology/Genomics</subject>
<subject>Evolutionary Biology/Bioinformatics</subject>
<subject>Evolutionary Biology/Microbial Evolution and Genomics</subject>
<subject>Genetics and Genomics/Bioinformatics</subject>
<subject>Molecular Biology/Bioinformatics</subject>
<subject>Virology/Emerging Viral Diseases</subject>
<subject>Infectious Diseases/Viral Infections</subject>
</subj-group>
</article-categories>
<title-group><article-title>Complete-Proteome Mapping of Human Influenza A Adaptive Mutations:
Implications for Human Transmissibility of Zoonotic Strains</article-title>
<alt-title alt-title-type="running-head">Human Influenza Adaptation Map</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Miotto</surname>
<given-names>Olivo</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Heiny</surname>
<given-names>A. T.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Albrecht</surname>
<given-names>Randy</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>García-Sastre</surname>
<given-names>Adolfo</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tan</surname>
<given-names>Tin Wee</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>August</surname>
<given-names>J. Thomas</given-names>
</name>
<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brusic</surname>
<given-names>Vladimir</given-names>
</name>
<xref ref-type="aff" rid="aff8"><sup>8</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Rajthevee, Bangkok, Thailand</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Department of Microbiology, Mount Sinai School of Medicine, New York, New York, United States of America</addr-line>
</aff>
<aff id="aff5"><label>5</label>
<addr-line>Division of Infectious Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America</addr-line>
</aff>
<aff id="aff6"><label>6</label>
<addr-line>Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York, United States of America</addr-line>
</aff>
<aff id="aff7"><label>7</label>
<addr-line>Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America</addr-line>
</aff>
<aff id="aff8"><label>8</label>
<addr-line>Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Poon</surname>
<given-names>Art F. Y.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">Providence Health Care, Canada</aff>
<author-notes><corresp id="cor1">* E-mail: <email>olivo.miotto@ndm.ox.ac.uk</email>
</corresp>
<fn fn-type="con"><p>Conceived and designed the experiments: OM TWT JTA VB. Performed the
experiments: OM ATH. Analyzed the data: OM RAA AGS TWT JTA VB. Contributed
reagents/materials/analysis tools: OM ATH. Wrote the paper: OM JTA VB.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2010</year>
</pub-date>
<pub-date pub-type="epub"><day>3</day>
<month>2</month>
<year>2010</year>
</pub-date>
<volume>5</volume>
<issue>2</issue>
<elocation-id>e9025</elocation-id>
<history><date date-type="received"><day>16</day>
<month>10</month>
<year>2009</year>
</date>
<date date-type="accepted"><day>27</day>
<month>12</month>
<year>2009</year>
</date>
</history>
<permissions><copyright-statement>Miotto et al.</copyright-statement>
<copyright-year>2010</copyright-year>
<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><sec><title>Background</title>
<p>There is widespread concern that H5N1 avian influenza A viruses will emerge
as a pandemic threat, if they become capable of human-to-human (H2H)
transmission. Avian strains lack this capability, which suggests that it
requires important adaptive mutations. We performed a large-scale
comparative analysis of proteins from avian and human strains, to produce a
catalogue of mutations associated with H2H transmissibility, and to detect
their presence in avian isolates.</p>
</sec>
<sec><title>Methodology/Principal Findings</title>
<p>We constructed a dataset of influenza A protein sequences from 92,343 public
database records. Human and avian sequence subsets were compared, using a
method based on <italic>mutual information</italic>
, to identify
<italic>characteristic sites</italic>
where human isolates present
conserved mutations. The resulting catalogue comprises 68 characteristic
sites in eight internal proteins. Subtype variability prevented the
identification of adaptive mutations in the hemagglutinin and neuraminidase
proteins. The high number of sites in the ribonucleoprotein complex suggests
interdependence between mutations in multiple proteins. Characteristic sites
are often clustered within known functional regions, suggesting their
functional roles in cellular processes. By isolating and concatenating
characteristic site residues, we defined <italic>adaptation
signatures</italic>
, which summarize the adaptive potential of specific
isolates. Most adaptive mutations emerged within three decades after the
1918 pandemic, and have remained remarkably stable thereafter. Two lineages
with stable internal protein constellations have circulated among humans
without reassorting. On the contrary, H5N1 avian and swine viruses reassort
frequently, causing both gains and losses of adaptive mutations.</p>
</sec>
<sec><title>Conclusions</title>
<p>Human host adaptation appears to be complex and systemic, involving nearly
all influenza proteins. Adaptation signatures suggest that the ability of
H5N1 strains to infect humans is related to the presence of an unusually
high number of adaptive mutations. However, these mutations appear unstable,
suggesting low pandemic potential of H5N1 in its current form. In addition,
adaptation signatures indicate that pandemic H1N1/09 strain possesses
multiple human-transmissibility mutations, though not an unusually high
number with respect to swine strains that infected humans in the past.
Adaptation signatures provide a novel tool for identifying zoonotic strains
with the potential to infect humans.</p>
</sec>
</abstract>
<counts><page-count count="13"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Royaume-Uni</li>
<li>Singapour</li>
<li>Thaïlande</li>
<li>États-Unis</li>
</country>
<region><li>Angleterre</li>
<li>Maryland</li>
<li>Massachusetts</li>
<li>Oxfordshire</li>
<li>État de New York</li>
</region>
<settlement><li>Oxford</li>
</settlement>
<orgName><li>Université d'Oxford</li>
<li>Université nationale de Singapour</li>
</orgName>
</list>
<tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Miotto, Olivo" sort="Miotto, Olivo" uniqKey="Miotto O" first="Olivo" last="Miotto">Olivo Miotto</name>
</region>
</country>
<country name="Thaïlande"><noRegion><name sortKey="Miotto, Olivo" sort="Miotto, Olivo" uniqKey="Miotto O" first="Olivo" last="Miotto">Olivo Miotto</name>
</noRegion>
</country>
<country name="Singapour"><noRegion><name sortKey="Heiny, A T" sort="Heiny, A T" uniqKey="Heiny A" first="A. T." last="Heiny">A. T. Heiny</name>
</noRegion>
<name sortKey="Tan, Tin Wee" sort="Tan, Tin Wee" uniqKey="Tan T" first="Tin Wee" last="Tan">Tin Wee Tan</name>
</country>
<country name="États-Unis"><region name="État de New York"><name sortKey="Albrecht, Randy" sort="Albrecht, Randy" uniqKey="Albrecht R" first="Randy" last="Albrecht">Randy Albrecht</name>
</region>
<name sortKey="August, J Thomas" sort="August, J Thomas" uniqKey="August J" first="J. Thomas" last="August">J. Thomas August</name>
<name sortKey="Brusic, Vladimir" sort="Brusic, Vladimir" uniqKey="Brusic V" first="Vladimir" last="Brusic">Vladimir Brusic</name>
<name sortKey="Garcia Sastre, Adolfo" sort="Garcia Sastre, Adolfo" uniqKey="Garcia Sastre A" first="Adolfo" last="García-Sastre">Adolfo García-Sastre</name>
<name sortKey="Garcia Sastre, Adolfo" sort="Garcia Sastre, Adolfo" uniqKey="Garcia Sastre A" first="Adolfo" last="García-Sastre">Adolfo García-Sastre</name>
<name sortKey="Garcia Sastre, Adolfo" sort="Garcia Sastre, Adolfo" uniqKey="Garcia Sastre A" first="Adolfo" last="García-Sastre">Adolfo García-Sastre</name>
</country>
</tree>
</affiliations>
</record>
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