PI3Kdelta regulation of influenza virus morbidity

由于流感病毒感染是老年人发病和死亡的重要原因，而目前的疫苗对老年人和幼儿的疗效有限，因此必须开发新的治疗方法，以减少与流感病毒感染相关的发病机制。为了实现这一目标，有必要更好地了解病毒与宿主的相互作用以及衰老对免疫系统的影响。制定减少与流感病毒感染相关的炎症的策略将降低发病率。我们建议研究一种名为PI3K的蛋白质分子在老年小鼠流感病毒感染期间炎症和病毒复制中的作用。使用PI3K在特定细胞类型中修饰的小鼠，我们将确定潜在的PI3K靶点，以改善与流感病毒感染相关的发病率。我们的初步数据表明，与感染流感病毒的对照组小鼠相比，感染流感病毒的PI3K-/-小鼠肺细胞浸润减少，发病率（体重减轻）降低，同时病毒复制减少，病毒清除不受影响。本文提出的研究将探讨抑制PI3K如何降低动物发病率，以及细胞和分子水平上的基础机制。我们的应用具有重要的转化潜力，因为它将确定降低流感病毒相关发病率的目标。由于对现有抗病毒药物的耐药性正在蔓延，确定和验证这些靶点至关重要。

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.