PI3Kdelta regulation of influenza virus morbidity

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Because influenza virus infection is an important cause of morbidity and mortality in the elderly and current vaccines have limited efficacy in the elderly and very young, it is imperative that new therapeutic approaches are developed to reduce pathogenesis associated with influenza virus infection. To achieve this, a greater understanding of the virus host interaction and the effects of ageing on the immune system are necessary. Devising strategies to reduce the inflammation associated with influenza virus infection would reduce morbidity. We propose to examine the role of a protein molecule called PI3K in inflammation and viral replication during influenza virus infection in aged mice. Using mice in which PI3K is modified in specific cell types we will identify potential PI3K targets that ameliorate the morbidity associated with influenza virus infection. Our preliminary data indicate that influenza virus infected PI3K-/-mice have a reduced lung cellular infiltrate and a reduced morbidity (weight loss) compared to influenza virus infected control mice, while viral replication is reduced and viral clearance remains unaffected. The studies proposed here will examine the how PI3K inhibition reduces morbidity in animals and the underpinning mechanism at the cellular and molecular level. Our application has important translational potential because it will identify targets to reduce influenza virus associated morbidity. The identification and validation of such targets is essential as resistance to existing antiviral is spreading.