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A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses.
J Virol. 2016 08 01; 90(15):6936-6947.JV

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.

Authors+Show Affiliations

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.Duke-NUS Medical School, Singapore.Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia kkedz@unimelb.edu.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

27226365

Citation

Quiñones-Parra, Sergio M., et al. "A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses." Journal of Virology, vol. 90, no. 15, 2016, pp. 6936-6947.
Quiñones-Parra SM, Clemens EB, Wang Z, et al. A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses. J Virol. 2016;90(15):6936-6947.
Quiñones-Parra, S. M., Clemens, E. B., Wang, Z., Croom, H. A., Kedzierski, L., McVernon, J., Vijaykrishna, D., & Kedzierska, K. (2016). A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses. Journal of Virology, 90(15), 6936-6947. https://doi.org/10.1128/JVI.00349-16
Quiñones-Parra SM, et al. A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses. J Virol. 2016 08 1;90(15):6936-6947. PubMed PMID: 27226365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Role of Influenza Virus Exposure History in Determining Pandemic Susceptibility and CD8+ T Cell Responses. AU - Quiñones-Parra,Sergio M, AU - Clemens,E Bridie, AU - Wang,Zhongfang, AU - Croom,Hayley A, AU - Kedzierski,Lukasz, AU - McVernon,Jodie, AU - Vijaykrishna,Dhanasekaran, AU - Kedzierska,Katherine, Y1 - 2016/07/11/ PY - 2016/02/24/received PY - 2016/05/12/accepted PY - 2016/5/27/entrez PY - 2016/5/27/pubmed PY - 2017/6/3/medline SP - 6936 EP - 6947 JF - Journal of virology JO - J Virol VL - 90 IS - 15 N2 - UNLABELLED: 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. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/27226365/A_Role_of_Influenza_Virus_Exposure_History_in_Determining_Pandemic_Susceptibility_and_CD8+_T_Cell_Responses_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27226365/ DB - PRIME DP - Unbound Medicine ER -