Autophagy regulation of RSV-induced pulmonary disease

摘要 肺中抗病毒免疫反应的调节依赖于有效和 正确识别致病信号，促进正确的、非致病的反应。 呼吸道合胞病毒(RSV)是一种特殊的致病病毒，可导致所有年龄段的人发病， 尤其是在婴儿和那些有潜在肺部疾病的人身上。我们最近公布的数据是从我们现在 资金周期表明，一条关键的先天性免疫途径具有调节致病作用的功能 免疫反应是自噬。这一无所不在的过程为所有细胞提供了不仅保存 资源，但将病原体成分运输到适当的免疫识别分子。特别是，这一点 这一过程似乎是树突状细胞激活、细胞因子产生和随后的T细胞的中心 激活。在这次更新中，我们将继续研究改变自噬的后果，包括 调节内质网应激和炎症体激活，导致固有细胞因子谱的明显变化。 我们将更加密切和机械地继续探索自噬诱导剂Sirtuin 1，a NAD+脱乙酰基酶，及其对自噬的调节作用，以及对直接和 对内质网应激和炎性小体激活有间接作用。将Sirt1-/-与抑制与Sirt1一起使用 过度表达和激活我们将探索Sirt1的缺失如何伴随自噬的减少 在体外和体内改变抗RSV的反应。内质网应激增加引起的细胞因子模式的改变 缺乏自噬和Sirt1可导致致病表型改变，这是由于增强的致病 T细胞反应，尤其是IL-17。因此，这些研究将探索几个新的和主题的路径，将 不仅进一步明确了促进肺粘膜免疫反应的机制，而且扩大了我们的 对呼吸道合胞病毒感染和免疫的认识。

Abstract The regulation of anti-viral immune responses in the lung is dependent upon the ability to efficiently and appropriately recognize pathogenic signals and promote the proper and non-pathogenic response. Respiratory syncytial virus (RSV) is an especially pathogenic virus that can induce morbidity at all ages, especially in infants and those with underlying lung conditions. Our recent data published from our present funding cycle indicated that a critical innate immune pathway that is functional for regulating pathogenic immune response is autophagy. This omnipresent process provides all cells the ability to not only preserve resources but transport pathogen components to the proper immune recognition molecules. In particular, this process appears to be central for dendritic cell activation, cytokine production, and subsequent T cell activation. In this renewal, we will continue to examine the consequences of altering autophagy, including the regulation of ER stress and inflammasome activation, that leads to a distinct shift in innate cytokine profiles. We will more closely and mechanistically continue to explore the role of an autophagy inducer, Sirtuin 1, a NAD+ deactylase, and its effect on the regulation of not only the autophagy profiles, but also the direct and indirect effect it has on ER stress and inflammasome activation. Using Sirt1 -/- and inhibition along with Sirt1 overexpression and activation we will explore how the absence of Sirt1 along with the reduction of autophagy alters anti-RSV responses in vitro and in vivo. The shift in cytokine patterns induced by increased ER stress in the absence of autophagy and Sirt1 can lead to an altered pathogenic phenotype due to enhanced pathogenic T cell responses, especially IL-17. Thus, these studies will explore several novel and topical pathways that will not only further define the mechanisms that promote pulmonary mucosal immune responses, but expand our understanding of RSV infection and immunity.