Microglia Response to Stress-induced HSV-1 Encephalitis

描述（由申请人提供）：虽然通常认为是不同的，但神经、内分泌和免疫系统密切相关。特别是，心理应激引起的下丘脑-垂体-肾上腺（HPA）轴的激活已显示出抑制外周对单纯疱疹病毒1型（HSV-1）的免疫应答。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CD 8 +T细胞浸润增加，随后发展为HSV-1脑炎（HSE）。然而，HSE期间CD 8 + T细胞浸润到脑中的潜在机制尚未阐明。拟议的研究旨在通过检查以下具体目标来确定小胶质细胞（中枢神经系统（CNS）的主要免疫介质）在HSE期间吸引和激活CD 8 +T细胞中的作用：（1）确定在应激诱导的HSE期间小胶质细胞TH 1/TH 2细胞因子和趋化因子的产生和（2）确定小胶质细胞MHC I类呈递和共-刺激分子在应激诱导的HSE。这些研究将验证以下假设：应激期间增强的小胶质细胞活化增加了HSV-1感染期间CD 8 +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TH 1细胞因子和趋化因子产生促炎环境，以及通过用MHC I类/肽复合物和共刺激分子激活T细胞来促进CD 8 + T细胞浸润。总的来说，拟议的研究将确定压力在HSV-1感染期间通过其对小胶质细胞活化的作用而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.