TLR7 mediates immune cell infiltration and homing to combat West Nile virus infec

描述（由申请人提供）：哺乳动物先天免疫是宿主防御包括病毒在内的入侵病原体的第一道防线。在宿主内，抗原呈递细胞如树突细胞和巨噬细胞表达多种模式识别受体（PRR），其识别微生物结构如核酸内的特异性病原体相关分子模式（PAMP）。通过PRR的信号传导导致产生多种细胞因子，包括促炎细胞因子、干扰素（IFN）和趋化因子，以控制病毒复制和传播。哺乳动物Toll样受体（Toll like receptor，Tlrs）由十多个成员组成，对多种PAMP具有特异性识别作用。西尼罗河病毒（West Nile virus，WNV）是一种能被Tlr 7识别的单链RNA病毒，在北美引起严重的人类和动物发病和死亡。我们的初步研究表明，Tlr 7缺陷（Tlr 7-/-）小鼠增加对WNV感染的易感性。此外，我们发现Tlr 7-/-免疫细胞（白细胞和巨噬细胞）不能归巢脑和肝脏中的WNV感染细胞，这可能解释了为什么Tlr 7-/-小鼠在WNV感染后增加死亡。此外，趋化因子和细胞因子阵列分析显示，Tlr 7-/-小鼠的巨噬细胞和血浆中白细胞介素-12/23p40（IL-12/23 p40）表达降低。此外，发现IL-23而不是IL-12能够吸引野生型巨噬细胞在体外迁移。在这个拟议的项目中，我们将剖析Tlr 7介导的免疫细胞迁移的机制，以打击西尼罗河病毒感染。具体目的1：进一步阐明WNV感染后Tlr 7-/-小鼠IL-23及其受体的表达。具体目的2：确定IL-23-/-小鼠是否在WNV感染后缺乏免疫细胞浸润和归巢。该项目不仅将扩大我们对Tlr 7- IL-23信号通路在控制WNV脑炎中的理解，而且可能导致针对WNV感染的新疗法。公共卫生相关性：本项目旨在研究Toll样受体7介导的免疫细胞浸润和归巢的机制，以对抗西尼罗河病毒脑炎小鼠模型中的西尼罗河病毒感染。

DESCRIPTION (provided by applicant): The mammalian innate immunity is the first line of the host defense against invading pathogens including viruses. Within the host, antigen-presenting cells such as dendritic cells and macrophages, express a variety of pattern recognition receptors (PRRs) that recognize specific pathogen-associated molecular patterns (PAMPs) within microbial structures such as nucleic acid. Signaling via PRRs leads to the production of a variety of cytokines including proinflammatory cytokines, interferons (IFNs) and chemokines to control viral replication and spread. The mammalian Toll-like receptors (Tlrs) that consist of more than ten members are curial for the recognition of a variety of PAMPs. West Nile virus (WNV), which has caused severe morbidity and mortality in humans and animals in North American, is a single-stranded RNA virus that can be recognized by Tlr7. Our preliminary studies demonstrated that Tlr7 deficient (Tlr7-/-) mice increase susceptibility to WNV infection. Moreover, we found that Tlr7-/- immune cells (leukocytes and macrophages) fail to home to WNV infected cells in brain and liver, which likely explains why Tlr7-/- mice increase death upon WNV infection. In addition, chemokine and cytokine array analysis showed that interleukin-12/23p40 (IL-12/23p40) expression was reduced in macrophages and plasma of Tlr7-/- mice. Furthermore, IL-23 but not IL-12 was found to be able to attract wild-type macrophages migration in vitro. In this proposed project, we will dissect the mechanisms underlying Tlr7-mediated immune cell migration to combat WNV infection. Specific Aim 1: Further delineate expression of IL-23 and its receptors in Tlr7 -/- mice after WNV infection. Specific Aim 2: Determine whether IL-23-/- mice are deficient in immune cell infiltration and homing after WNV infection. This project will not only expand our understanding of Tlr7 - IL-23 signaling pathway in control of WNV encephalitis, but may result in new therapeutics against WNV infection. PUBLIC HEALTH RELEVANCE: This project is to dissect the mechanisms underlying Toll-like Receptor 7- mediated immune cell infiltration and homing to combat West Nile virus infection in the murine model of West Nile virus encephalitis.