Influenza A virus (IAV) infections have claimed over 50 million lives worldwide during epidemic and pandemics. Patients with asthma were less likely to suffer from severe influenza during the 2009 influenza pandemic compared to non-asthmatics for reasons not yet fully elucidated. We have recapitulated these clinical findings using our innovative mouse model of asthma and influenza co-morbidity, and found that heightened eosinophilia during influenza infection correlated with reduced lung viral burden. Our preliminary data showed that eosinophil transfer into lungs of virus-infected animals reduced lung viral burden and led to increased recruitment of CD8+ T-cells into the airways. Mice in the asthma and influenza co-morbidity model also have elevated gene expression of resistin-like molecule (RELM)-? and -?, and the administration of these proteins into the lungs of virus-infected mice led to a reduction in lung viral burden and increased recruitment of CD8+ T-cells. These data led to our central hypothesis that eosinophils in allergic airways promote antiviral immunity against IAV by activating CD8+ T-cells. The three overlapping aims to be investigated in this project are: (1) To identify eosinophil granule proteins released during degranulation upon direct contact with IAV and determine their impact on IAV infectivity, (2) To determine if eosinophils directly enhance CD8+ T-cell responses against IAV, and (3) To determine the function of eosinophil-derived RELM proteins in enhancing antiviral immunity against IAV. This project is significant because we propose to identify basic immune mechanisms in host defense against a prominent human pathogen with an innovative approach of investigating eosinophils as a regulator of adaptive immunity and mediator of host protection rather than as an end-stage effector cell. These studies will have a broad impact on eosinophil biology, virology, and may offer novel therapeutic targets to treat influenza.
We propose studies to investigate the mechanisms by which eosinophils regulate antiviral host immunity against influenza A virus. These studies are relevant to public health because they will provide mechanistic insight into anti-influenza immunity in hosts with allergic asthma. Evidence of cytotoxic T-cell regulation by eosinophils will be broadly applicable to immunology and other diseases.
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