Diverse Heterologous Primary Infections Radically Alter Immunodominance Hierarchies and Clinical Outcomes Following H7N9 Influenza Challenge in Mice

PLoS Pathogens

Peter C. Doherty¹  Jennifer L. McClaren¹  Susu Duan¹  Catherine J. Sanders¹  Xi-Zhi J. Guo¹  Heather S. Smallwood¹  Paul G. Thomas¹  Stacey L. Schultz-Cherry²  Victoria A. Meliopoulos²  Richard J. Webby² 

[1] Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America;Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America

关键词: H7N9;    Influenza A virus;    Memory;    Priming (psychology);    H1N1;    Immune response;    T cells;    Mouse models;   

DOI  :  10.1371/journal.ppat.1004642

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The recent emergence of a novel H7N9 influenza A virus (IAV) causing severe human infections in China raises concerns about a possible pandemic. The lack of pre-existing neutralizing antibodies in the broader population highlights the potential protective role of IAV-specific CD8+ cytotoxic T lymphocyte (CTL) memory specific for epitopes conserved between H7N9 and previously encountered IAVs. In the present study, the heterosubtypic immunity generated by prior H9N2 or H1N1 infections significantly, but variably, reduced morbidity and mortality, pulmonary virus load and time to clearance in mice challenged with the H7N9 virus. In all cases, the recall of established CTL memory was characterized by earlier, greater airway infiltration of effectors targeting the conserved or cross-reactive H7N9 IAV peptides; though, depending on the priming IAV, each case was accompanied by distinct CTL epitope immunodominance hierarchies for the prominent KbPB1703, DbPA224, and DbNP366 epitopes. While the presence of conserved, variable, or cross-reactive epitopes between the priming H9N2 and H1N1 and the challenge H7N9 IAVs clearly influenced any change in the immunodominance hierarchy, the changing patterns were not tied solely to epitope conservation. Furthermore, the total size of the IAV-specific memory CTL pool after priming was a better predictor of favorable outcomes than the extent of epitope conservation or secondary CTL expansion. Modifying the size of the memory CTL pool significantly altered its subsequent protective efficacy on disease severity or virus clearance, confirming the important role of heterologous priming. These findings establish that both the protective efficacy of heterosubtypic immunity and CTL immunodominance hierarchies are reflective of the immunological history of the host, a finding that has implications for understanding human CTL responses and the rational design of CTL-mediated vaccines.

【 授权许可】

CC BY