Microglia Response to Stress-induced HSV-1 Encephalitis

描述（由申请人提供）：尽管通常认为神经系统、内分泌系统和免疫系统是不同的，但它们是密切相关的。特别是，心理应激对下丘脑-垂体-肾上腺（HPA）轴的激活已被证明可以抑制外周对1型单纯疱疹病毒（HSV-1）的免疫反应。然而，先前的研究表明，应激增加了大脑中对HSV-1的免疫反应，导致CD8+T细胞浸润增加，随后发展为HSV-1脑炎（HSE）。然而，在HSE期间CD8+ T细胞渗入大脑的机制尚未阐明。本研究旨在确定小胶质细胞作为中枢神经系统（CNS）的主要免疫介质，在HSE过程中对CD8+T细胞的吸引和激活中的作用，具体目的如下：(1)测定应激诱导HSE过程中小胶质细胞TH1/TH2细胞因子和趋化因子的产生；(2)测定应激诱导HSE过程中小胶质细胞MHC类共刺激分子的呈现和表达。这些研究将验证应激条件下小胶质细胞活化的增强会增加HSV-1感染期间CD8+T细胞的浸润和活化，从而促进HSE的发展。小胶质细胞可能通过产生TH1细胞因子和趋化因子产生促炎环境，以及通过激活具有MHC I类/肽复合物和共刺激分子的T细胞来促进CD8+ T细胞浸润。总的来说，拟议的研究将通过其对小胶质细胞激活的作用来确定应激在HSV-1感染期间增强神经炎症的作用。

DESCRIPTION (provided by applicant): Although generally thought of as distinct, the nervous, endocrine, and immune systems are intimately related. In particular, the activation of the hypothalamic-pituitary-adrenal (HPA) axis by psychological stress has been shown to inhibit the immune response to herpes simplex virus type-1 (HSV-1) in the periphery. However, previous studies have shown that stress increases the immune response to HSV-1 in the brain, resulting in increased CD8+T cell infiltration and the subsequent development of HSV-1 encephalitis (HSE). The mechanisms underlying the infiltration of CD8+ T cells into the brain during HSE, however, have not yet been elucidated. The proposed research seeks to determine the role of microglia, the primary immune mediators of the central nervous system (CNS), in the attraction and activation of CD8+T cells during HSE by examining the following specific aims: (1) To determine microglia TH1/TH2 cytokine and chemokine production during stress-induced HSE and (2) To determine microglia MHC class I presentation and expression of co-stimulatory molecules during stress-induced HSE. These studies will test the hypothesis that enhanced microglia activation during stress increases the infiltration and activation of CD8+T cells during HSV-1 infection, thus promoting the development of HSE. Microglia may contribute to CD8+ T cell infiltration by generating a pro-inflammatory environment through TH1 cytokine and chemokine production, as well as by activating T cells with MHC class I/peptide complexes and costimulatory molecules. Overall, the proposed studies will determine the role of stress in enhancing neuroinflammation during HSV-1 infection through its actions on microglia activation.