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A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses

Identifieur interne : 000060 ( Pmc/Curation ); précédent : 000059; suivant : 000061

A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses

Auteurs : Sergio M. Qui Ones-Parra [Australie] ; E. Bridie Clemens [Australie] ; Zhongfang Wang [Australie] ; Hayley A. Croom [Australie] ; Lukasz Kedzierski [Australie] ; Jodie Mcvernon [Australie] ; Dhanasekaran Vijaykrishna [Singapour] ; Katherine Kedzierska [Australie]

Source :

RBID : PMC:4944292

Abstract

ABSTRACT

Novel influenza viruses often cause differential infection patterns across different age groups, an effect that is defined as heterogeneous demographic susceptibility. This occurred during the A/H2N2 pandemic, when children experienced higher influenza attack rates than adults. Since the recognition of conserved epitopes across influenza subtypes by CD8+ cytotoxic T lymphocytes (CTLs) limit influenza disease, we hypothesized that conservation of CTL antigenic peptides (Ag-p) in viruses circulating before the pH2N2-1957 may have resulted in differential CTL immunity. We compared viruses isolated in the years preceding the pandemic (1941 to 1957) to which children and adults were exposed to viruses circulating decades earlier (1918 to 1940), which could infect adults only. Consistent with phylogenetic models, influenza viruses circulating from 1941 to 1957, which infected children, shared with pH2N2 the majority (∼89%) of the CTL peptides within the most immunogenic nucleoprotein, matrix 1, and polymerase basic 1, thus providing evidence for minimal pH2N2 CTL escape in children. Our study, however, identified potential CTL immune evasion from pH2N2 irrespective of age, within HLA-A*03:01+ individuals for PB1471-L473V/N476I variants and HLA-B*15:01+ population for NP404–414-V408I mutant. Further experiments using the murine model of B-cell-deficient mice showed that multiple influenza infections resulted in superior protection from influenza-induced morbidity, coinciding with accumulation of tissue-resident memory CD8+ T cells in the lung. Our study suggests that protection against H2N2-1957 pandemic influenza was most likely linked to the number of influenza virus infections prior to the pandemic challenge rather than differential preexisting CTL immunity. Thus, the regimen of a CTL-based vaccine/vaccine-component may benefit from periodic boosting to achieve fully protective, asymptomatic influenza infection.

IMPORTANCE Due to a lack of cross-reactive neutralizing antibodies, children are particularly susceptible to influenza infections caused by novel viral strains. Preexisting T cell immunity directed at conserved viral regions, however, can provide protection against influenza viruses, promote rapid recovery and better clinical outcomes. When we asked whether high susceptibility of children (compared to adults) to the pandemic H2N2 influenza strain was associated with immune evasion from T-cell immunity, we found high conservation within T-cell antigenic regions in pandemic H2N2. However, the number of influenza infections prior to the challenge was linked to protective, asymptomatic infections and establishment of tissue-resident memory T cells. Our study supports development of vaccines that prime and boost T cells to elicit cross-strain protective T cells, especially tissue-resident memory T cells, for lifelong immunity against distinct influenza viruses.


Url:
DOI: 10.1128/JVI.00349-16
PubMed: 27226365
PubMed Central: 4944292

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<title>ABSTRACT</title>
<p>Novel influenza viruses often cause differential infection patterns across different age groups, an effect that is defined as heterogeneous demographic susceptibility. This occurred during the A/H2N2 pandemic, when children experienced higher influenza attack rates than adults. Since the recognition of conserved epitopes across influenza subtypes by CD8
<sup>+</sup>
cytotoxic T lymphocytes (CTLs) limit influenza disease, we hypothesized that conservation of CTL antigenic peptides (Ag-p) in viruses circulating before the pH2N2-1957 may have resulted in differential CTL immunity. We compared viruses isolated in the years preceding the pandemic (1941 to 1957) to which children and adults were exposed to viruses circulating decades earlier (1918 to 1940), which could infect adults only. Consistent with phylogenetic models, influenza viruses circulating from 1941 to 1957, which infected children, shared with pH2N2 the majority (∼89%) of the CTL peptides within the most immunogenic nucleoprotein, matrix 1, and polymerase basic 1, thus providing evidence for minimal pH2N2 CTL escape in children. Our study, however, identified potential CTL immune evasion from pH2N2 irrespective of age, within HLA-A*03:01
<sup>+</sup>
individuals for PB1
<sub>471</sub>
-L473V/N476I variants and HLA-B*15:01
<sup>+</sup>
population for NP
<sub>404–414</sub>
-V408I mutant. Further experiments using the murine model of B-cell-deficient mice showed that multiple influenza infections resulted in superior protection from influenza-induced morbidity, coinciding with accumulation of tissue-resident memory CD8
<sup>+</sup>
T cells in the lung. Our study suggests that protection against H2N2-1957 pandemic influenza was most likely linked to the number of influenza virus infections prior to the pandemic challenge rather than differential preexisting CTL immunity. Thus, the regimen of a CTL-based vaccine/vaccine-component may benefit from periodic boosting to achieve fully protective, asymptomatic influenza infection. </p>
<p>
<bold>IMPORTANCE</bold>
Due to a lack of cross-reactive neutralizing antibodies, children are particularly susceptible to influenza infections caused by novel viral strains. Preexisting T cell immunity directed at conserved viral regions, however, can provide protection against influenza viruses, promote rapid recovery and better clinical outcomes. When we asked whether high susceptibility of children (compared to adults) to the pandemic H2N2 influenza strain was associated with immune evasion from T-cell immunity, we found high conservation within T-cell antigenic regions in pandemic H2N2. However, the number of influenza infections prior to the challenge was linked to protective, asymptomatic infections and establishment of tissue-resident memory T cells. Our study supports development of vaccines that prime and boost T cells to elicit cross-strain protective T cells, especially tissue-resident memory T cells, for lifelong immunity against distinct influenza viruses.</p>
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<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>
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<subject>Pathogenesis and Immunity</subject>
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<title-group>
<article-title>A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8
<sup>+</sup>
T Cell Responses</article-title>
<alt-title alt-title-type="running-head">CTL Immunity and Influenza Pandemics</alt-title>
<alt-title alt-title-type="short-authors">Quiñones-Parra et al.</alt-title>
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<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Quiñones-Parra</surname>
<given-names>Sergio M.</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Clemens</surname>
<given-names>E. Bridie</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Zhongfang</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Croom</surname>
<given-names>Hayley A.</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kedzierski</surname>
<given-names>Lukasz</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>McVernon</surname>
<given-names>Jodie</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Vijaykrishna</surname>
<given-names>Dhanasekaran</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Kedzierska</surname>
<given-names>Katherine</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
</contrib>
<aff id="aff1">
<label>a</label>
Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia</aff>
<aff id="aff2">
<label>b</label>
The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia</aff>
<aff id="aff3">
<label>c</label>
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia</aff>
<aff id="aff4">
<label>d</label>
Duke-NUS Medical School, Singapore</aff>
</contrib-group>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Perlman</surname>
<given-names>S.</given-names>
</name>
<role>Editor</role>
</contrib>
<aff>University of Iowa</aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Address correspondence to Katherine Kedzierska,
<email>kkedz@unimelb.edu.au</email>
.</corresp>
<fn fn-type="other">
<p>
<bold>Citation</bold>
Quiñones-Parra SM, Clemens EB, Wang Z, Croom HA, Kedzierski L, Mcvernon J, Vijaykrishna D, Kedzierska K. 2016. A role of influenza virus exposure history in determining pandemic susceptibility and CD8
<sup>+</sup>
T cell responses. J Virol 90:6936–6947. doi:
<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1128/JVI.00349-16">10.1128/JVI.00349-16</ext-link>
.</p>
</fn>
</author-notes>
<pub-date pub-type="epreprint">
<day>25</day>
<month>5</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub">
<day>11</day>
<month>7</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection">
<day>1</day>
<month>8</month>
<year>2016</year>
</pub-date>
<volume>90</volume>
<issue>15</issue>
<fpage>6936</fpage>
<lpage>6947</lpage>
<history>
<date date-type="received">
<day>24</day>
<month>2</month>
<year>2016</year>
</date>
<date date-type="accepted">
<day>12</day>
<month>5</month>
<year>2016</year>
</date>
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<permissions>
<copyright-statement>Copyright © 2016, American Society for Microbiology. All Rights Reserved.</copyright-statement>
<copyright-year>2016</copyright-year>
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</permissions>
<self-uri content-type="pdf" xlink:href="zjv01516006936.pdf"></self-uri>
<abstract>
<title>ABSTRACT</title>
<p>Novel influenza viruses often cause differential infection patterns across different age groups, an effect that is defined as heterogeneous demographic susceptibility. This occurred during the A/H2N2 pandemic, when children experienced higher influenza attack rates than adults. Since the recognition of conserved epitopes across influenza subtypes by CD8
<sup>+</sup>
cytotoxic T lymphocytes (CTLs) limit influenza disease, we hypothesized that conservation of CTL antigenic peptides (Ag-p) in viruses circulating before the pH2N2-1957 may have resulted in differential CTL immunity. We compared viruses isolated in the years preceding the pandemic (1941 to 1957) to which children and adults were exposed to viruses circulating decades earlier (1918 to 1940), which could infect adults only. Consistent with phylogenetic models, influenza viruses circulating from 1941 to 1957, which infected children, shared with pH2N2 the majority (∼89%) of the CTL peptides within the most immunogenic nucleoprotein, matrix 1, and polymerase basic 1, thus providing evidence for minimal pH2N2 CTL escape in children. Our study, however, identified potential CTL immune evasion from pH2N2 irrespective of age, within HLA-A*03:01
<sup>+</sup>
individuals for PB1
<sub>471</sub>
-L473V/N476I variants and HLA-B*15:01
<sup>+</sup>
population for NP
<sub>404–414</sub>
-V408I mutant. Further experiments using the murine model of B-cell-deficient mice showed that multiple influenza infections resulted in superior protection from influenza-induced morbidity, coinciding with accumulation of tissue-resident memory CD8
<sup>+</sup>
T cells in the lung. Our study suggests that protection against H2N2-1957 pandemic influenza was most likely linked to the number of influenza virus infections prior to the pandemic challenge rather than differential preexisting CTL immunity. Thus, the regimen of a CTL-based vaccine/vaccine-component may benefit from periodic boosting to achieve fully protective, asymptomatic influenza infection. </p>
<p>
<bold>IMPORTANCE</bold>
Due to a lack of cross-reactive neutralizing antibodies, children are particularly susceptible to influenza infections caused by novel viral strains. Preexisting T cell immunity directed at conserved viral regions, however, can provide protection against influenza viruses, promote rapid recovery and better clinical outcomes. When we asked whether high susceptibility of children (compared to adults) to the pandemic H2N2 influenza strain was associated with immune evasion from T-cell immunity, we found high conservation within T-cell antigenic regions in pandemic H2N2. However, the number of influenza infections prior to the challenge was linked to protective, asymptomatic infections and establishment of tissue-resident memory T cells. Our study supports development of vaccines that prime and boost T cells to elicit cross-strain protective T cells, especially tissue-resident memory T cells, for lifelong immunity against distinct influenza viruses.</p>
</abstract>
<funding-group>
<funding-statement>This work was supported by Australian National Health and Medical Research Council (NHMRC) project grant GNT1008854 and program grant GNT1071916 to Katherine Kedzierska. Sergio M. Quiñones-Parra was supported by a University of Melbourne International Research Scholarship and was a CONACyT scholar. Dhanasekaran Vijaykrishna is supported by the Duke-NUS Signature Research Program funded by the Agency of Science, Technology and Research, Singapore, and the Ministry of Health, Singapore, and by contract HHSN272201400006C from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, USA.</funding-statement>
</funding-group>
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