Abstract
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.
Highlights
Human infections with a novel, avian-origin H7N9 influenza A virus (IAV) were first seen in Southeast China in April 2013[1], re-emerged through the 2013 winter and spread to other regions [2]
Our study found that previous infection with nonH7N9 subtype viruses such as H9N2 viruses or H1N1 viruses could provide protection against lethal H7N9 challenge to varying degrees in mice
The virus-specific memory CD8+ T cells generated by the previous infection but targeting conserved or related portions of the internal proteins of the H7N9 viruses were selectively expanded and recruited at very early time points after H7N9 challenge, contributing to protective efficacy
Summary
Human infections with a novel, avian-origin H7N9 influenza A virus (IAV) were first seen in Southeast China in April 2013[1], re-emerged through the 2013 winter and spread to other regions [2]. The severity of infection, the potential for transmission between humans, and the absence of neutralizing immunity raise serious concerns about a possible pandemic. This concern once again emphasizes the importance of cross-subtype protective mechanisms against influenza infection. There are indications [10,11,12,13] that prior infection with seasonal IAVs in humans can generate a measure of cross-reactive, or “heterosubtypic”, CD8+ cytotoxic T lymphocyte (CTL)-mediated immunity against further infection with other, serologically distinct seasonal or pandemic IAVs but, because of the limited case numbers to date, our understanding of how that plays out for H7N9 infection is rudimentary
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