Control of Influenza Infection by Lipid Mediators and Macrophages

摘要 甲型流感病毒(IAV)是一种主要的人类病原体，具有在世界范围内迅速传播和 导致以严重肺炎为特征的严重的、有时是致命的肺部感染。疾病严重程度 反映了病毒在呼吸道细胞中复制的程度，以及 宿主先天和获得性免疫反应的强度或大小。因此，宿主的免疫反应是 不仅负责IAV的清除，而且在感染过程中还会造成组织损伤。然而，虽然 免疫细胞在消除病毒中的作用是有据可查的，免疫细胞的作用，特别是先天的作用 免疫细胞在调节体内呼吸道细胞对IAV感染易感性中的作用较差 明白了。我们最近在一种新的IAV感染小鼠模型中报道了半胱氨酸基的上调 终末呼吸道(肺泡)上皮细胞白三烯(5-脂氧合酶)代谢途径与 这些细胞对IAV感染的易感性增强。此外，终末气道滞留(肺泡) 巨噬细胞抑制终末呼吸道上皮细胞5-脂氧合酶途径的上调 因此，降低细胞对IAV感染的易感性。本文件中描述的程序 应用旨在探索5-脂氧合酶代谢途径的作用和通过半胱氨酸基的信号转导 白三烯受体在控制呼吸道上皮细胞对IAV感染敏感性中的作用 终末呼吸道巨噬细胞降低易感性的机制。我们将制定以下要求 终末呼吸道上皮细胞5-脂氧合酶途径酶活性与半胱氨酰白三烯受体信号转导 细胞，并探索通过该受体传递信号增强对IAV易感性的机制 感染(目标1)。同时，我们将探讨终末呼吸道巨噬细胞与呼吸道之间的相互作用。 上皮细胞和IAV导致呼吸道上皮细胞对感染易感性的抑制， 巨噬细胞作用导致抑制的机制，并将这一分析扩展到人类(目标2)。

Abstract Type A influenza virus (IAV) is a major human pathogen with the capacity to rapidly spread worldwide and to produce severe and sometimes fatal lung infections characterized by severe pneumonia. Disease severity resulting from IAV infection reflects the extent of virus replication in cells of the respiratory tract and the strength or magnitude of the host innate and adaptive immune response. Thus, the host immune response is not only responsible for IAV clearance but also contributes to tissue injury during infection. However, while the role of immune cells in virus elimination is well documented, the role of immune cells and in particular innate immune cells in regulating the susceptibility of respiratory tract cells in vivo to IAV infection is only poorly understood. We recently reported in a novel mouse model of IAV infection that upregulation of the cysteinyl leukotriene (5-lipoxygenase) metabolic pathway in terminal airway (alveolar) epithelial cells is associated with enhanced susceptibility of these cells to IAV infection. Furthermore, terminal airway resident (alveolar) macrophages suppress the upregulation of the 5-lipoxygenase pathway in terminal airway epithelial cells and as a consequence reduce the susceptibility of the cells to IAV infection. The program described in this application is designed to explore the role of the 5-lipoxygenase metabolic pathway and signaling via cysteinyl leukotriene receptors in controlling the susceptibility of airway epithelial cells to IAV infection and the mechanism by which terminal airway macrophages reduce susceptibility. We will establish the requirement for 5-lipoxygenase pathway enzymatic activity, cysteinyl leukotriene receptor signaling in terminal airway epithelial cells and explore the mechanism by which signaling through this receptor enhances susceptibility to IAV infection (Aim 1). In conjunction, we will explore the interaction between terminal airway macrophages, airway epithelial cells and IAV resulting in suppression of susceptibility of airway epithelial cells to infection, the mechanism of macrophage action leading to suppression and extend this analysis into the human (Aim 2).