Long-term adaptation of the influenza A virus by escaping cytotoxic T-cell recognition
Identifieur interne : 000105 ( Pmc/Curation ); précédent : 000104; suivant : 000106Long-term adaptation of the influenza A virus by escaping cytotoxic T-cell recognition
Auteurs : Rutger G. Woolthuis [Pays-Bas] ; Christiaan H. Van Dorp [Pays-Bas] ; Can Ke Mir [Pays-Bas] ; Rob J. De Boer [Pays-Bas] ; Michiel Van Boven [Pays-Bas]Source :
- Scientific Reports [ 2045-2322 ] ; 2016.
Abstract
The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised. Much less is known about the long-term evolution of cytotoxic T lymphocyte (CTL) epitopes, which are important antigens for clearance of infection. We construct an antigenic map of IAVs of all human subtypes using a compendium of 142 confirmed CTL epitopes, and show that IAV evolved gradually in the period 1932–2015, with infrequent antigenic jumps in the H3N2 subtype. Intriguingly, the number of CTL epitopes per virus decreases with more than one epitope per three years in the H3N2 subtype (from 84 epitopes per virus in 1968 to 64 in 2015), mostly attributed to the loss of HLA-B epitopes. We confirm these observations with epitope predictions. Our findings indicate that selection pressures imposed by CTL immunity shape the long-term evolution of IAV.
Url:
DOI: 10.1038/srep33334
PubMed: 27629812
PubMed Central: 5024124
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Woolthuis</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>National Institute for Public Health and the Environment</institution>, Bilthoven,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Dorp, Christiaan H" sort="Van Dorp, Christiaan H" uniqKey="Van Dorp C" first="Christiaan H." last="Van Dorp">Christiaan H. Van Dorp</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>National Institute for Public Health and the Environment</institution>, Bilthoven,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ke Mir, Can" sort="Ke Mir, Can" uniqKey="Ke Mir C" first="Can" last="Ke Mir">Can Ke Mir</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="De Boer, Rob J" sort="De Boer, Rob J" uniqKey="De Boer R" first="Rob J." last="De Boer">Rob J. De Boer</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Boven, Michiel" sort="Van Boven, Michiel" uniqKey="Van Boven M" first="Michiel" last="Van Boven">Michiel Van Boven</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>National Institute for Public Health and the Environment</institution>, Bilthoven,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27629812</idno><idno type="pmc">5024124</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024124</idno><idno type="RBID">PMC:5024124</idno><idno type="doi">10.1038/srep33334</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000105</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000105</idno><idno type="wicri:Area/Pmc/Curation">000105</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000105</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Long-term adaptation of the influenza A virus by escaping cytotoxic T-cell recognition</title><author><name sortKey="Woolthuis, Rutger G" sort="Woolthuis, Rutger G" uniqKey="Woolthuis R" first="Rutger G." last="Woolthuis">Rutger G. Woolthuis</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>National Institute for Public Health and the Environment</institution>, Bilthoven,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Dorp, Christiaan H" sort="Van Dorp, Christiaan H" uniqKey="Van Dorp C" first="Christiaan H." last="Van Dorp">Christiaan H. Van Dorp</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>National Institute for Public Health and the Environment</institution>, Bilthoven,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ke Mir, Can" sort="Ke Mir, Can" uniqKey="Ke Mir C" first="Can" last="Ke Mir">Can Ke Mir</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="De Boer, Rob J" sort="De Boer, Rob J" uniqKey="De Boer R" first="Rob J." last="De Boer">Rob J. De Boer</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Boven, Michiel" sort="Van Boven, Michiel" uniqKey="Van Boven M" first="Michiel" last="Van Boven">Michiel Van Boven</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>National Institute for Public Health and the Environment</institution>, Bilthoven,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised. Much less is known about the long-term evolution of cytotoxic T lymphocyte (CTL) epitopes, which are important antigens for clearance of infection. We construct an antigenic map of IAVs of all human subtypes using a compendium of 142 confirmed CTL epitopes, and show that IAV evolved gradually in the period 1932–2015, with infrequent antigenic jumps in the H3N2 subtype. Intriguingly, the number of CTL epitopes per virus decreases with more than one epitope per three years in the H3N2 subtype (from 84 epitopes per virus in 1968 to 64 in 2015), mostly attributed to the loss of HLA-B epitopes. We confirm these observations with epitope predictions. Our findings indicate that selection pressures imposed by CTL immunity shape the long-term evolution of IAV.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Van De Sandt, C E" uniqKey="Van De Sandt C">C. 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<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</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27629812</article-id><article-id pub-id-type="pmc">5024124</article-id><article-id pub-id-type="pii">srep33334</article-id><article-id pub-id-type="doi">10.1038/srep33334</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Long-term adaptation of the influenza A virus by escaping cytotoxic T-cell recognition</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Woolthuis</surname><given-names>Rutger G.</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>van Dorp</surname><given-names>Christiaan H.</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Keşmir</surname><given-names>Can</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>de Boer</surname><given-names>Rob J.</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>van Boven</surname><given-names>Michiel</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><aff id="a1"><label>1</label><institution>Theoretical Biology, Utrecht University</institution>, Utrecht,<country>The Netherlands</country></aff><aff id="a2"><label>2</label><institution>National Institute for Public Health and the Environment</institution>, Bilthoven,<country>The Netherlands</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>rutger@woolthuis.nl</email></corresp><fn id="n1"><label>*</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="epub"><day>15</day><month>09</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>6</volume><elocation-id>33334</elocation-id><history><date date-type="received"><day>01</day><month>06</month><year>2016</year></date><date date-type="accepted"><day>23</day><month>08</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016, The Author(s)</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. 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><p>The evolutionary adaptation of the influenza A virus (IAV) to human antibodies is well characterised. Much less is known about the long-term evolution of cytotoxic T lymphocyte (CTL) epitopes, which are important antigens for clearance of infection. We construct an antigenic map of IAVs of all human subtypes using a compendium of 142 confirmed CTL epitopes, and show that IAV evolved gradually in the period 1932–2015, with infrequent antigenic jumps in the H3N2 subtype. Intriguingly, the number of CTL epitopes per virus decreases with more than one epitope per three years in the H3N2 subtype (from 84 epitopes per virus in 1968 to 64 in 2015), mostly attributed to the loss of HLA-B epitopes. We confirm these observations with epitope predictions. Our findings indicate that selection pressures imposed by CTL immunity shape the long-term evolution of IAV.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>CTL epitope evolution in the influenza A virus.</title><p>Antigenic map of 295 representative influenza A viruses spanning the period 1932–2015 (□H1N1, △H2N2, ○H3N2, <inline-formula id="d33e765"><inline-graphic id="d33e766" xlink:href="srep33334-m15.jpg"></inline-graphic></inline-formula> pH1N1) based on 134 CTL epitopes. The H3N2 subtype has evolved extensively over the period 1968–2015, while the H2N2 and H3N2 viruses circulating in the late 1960s are antigenically close. Recent avian viruses are superimposed independently onto the antigenic map (<inline-formula id="d33e768"><inline-graphic id="d33e769" xlink:href="srep33334-m16.jpg"></inline-graphic></inline-formula> H5N1, <inline-formula id="d33e771"><inline-graphic id="d33e772" xlink:href="srep33334-m17.jpg"></inline-graphic></inline-formula> H7N9 and <inline-formula id="d33e774"><inline-graphic id="d33e775" xlink:href="srep33334-m18.jpg"></inline-graphic></inline-formula> H9N2), using the 134 CTL epitopes of human IAV origin. The map is constructed using multi-dimensional scaling (MDS) based on Jaccard distances, explaining 93% of the antigenic distances (Methods). Scale bar denotes expected differences in the number of epitopes; colours indicate collection year of the virus.</p></caption><graphic xlink:href="srep33334-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Decrease in the number of CTL epitopes over time.</title><p>(<bold>a</bold>) The number of CTL epitopes per virus decreases with 0.14 ± 0.01, 0.20 ± 0.06, and 0.40 ± 0.02, epitopes per year (SEM) in H1N1, H2N2, and H3N2, respectively (Methods). The number of CTL epitopes in avian viruses is larger than in recent human viruses (<inline-formula id="d33e786"><inline-graphic id="d33e787" xlink:href="srep33334-m19.jpg"></inline-graphic></inline-formula> H5N1, <inline-formula id="d33e789"><inline-graphic id="d33e790" xlink:href="srep33334-m20.jpg"></inline-graphic></inline-formula> H7N9 and <inline-formula id="d33e792"><inline-graphic id="d33e793" xlink:href="srep33334-m21.jpg"></inline-graphic></inline-formula> H9N2). (<bold>b</bold>) Protein specific CTL epitope dynamics showing a decrease in the number of epitopes in NP, matrix 1 protein (M1) and non-structural protein (NS1). The other IAV proteins are laid down in <xref ref-type="supplementary-material" rid="S1">Supplementary Fig. S10</xref>. Reassortment events resulting in the appearance of novel proteins are marked by triangles. Subtype replacements are marked by vertical lines. The analysis is based on 7,347 whole-proteome sequenced viruses (Methods).</p></caption><graphic xlink:href="srep33334-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Decrease in the number of predicted epitopes.</title><p>The change in number of top 5% strongest binding peptides in NP of H3N2 viruses for HLA-A (<bold>a</bold>) and HLA-B (<bold>b</bold>) alleles is shown over the period 1968–2015 (histograms; Methods). These peptides decrease in number for the large majority of HLA-B alleles (P = 0.006; mean change <inline-formula id="d33e814"><inline-graphic id="d33e815" xlink:href="srep33334-m14.jpg"></inline-graphic></inline-formula> (95% CI: −15.6%, −2.6%) over the study period, Methods), but not for HLA-A alleles (P = 0.46). Despite the high level of heterogeneity in binding motifs, we find a decrease in the number of top-binders for a broad range of HLA-B alleles (<xref ref-type="supplementary-material" rid="S1">Supplementary Fig. S12</xref>). The position of the twelve HLA supertype representatives are indicated with arrows. Fitted Gaussian curves indicate the decrease calculated for the thresholds ≤5%, ≤10% (top binders), and ≥50% (weak binders).</p></caption><graphic xlink:href="srep33334-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>CTL epitope dynamics.</title><p>Epitopes appear and disappear continuously in H1N1 (<bold>a</bold>) and H2N2-H3N2 (<bold>b</bold>), with the highest turnover in NP. Within years epitope gains and losses are correlated, due to annual variation in genetic drift. We calculate for each epitope the difference in the fraction of viruses harbouring the epitope in a given year and the year before. Summing over all positive (negative) differences of the fractions gives the total gain (loss).</p></caption><graphic xlink:href="srep33334-f4"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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