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

描述（由申请人提供）：哺乳动物的先天免疫是宿主抵御包括病毒在内的病原体入侵的第一道防线。在宿主体内，抗原呈递细胞如树突状细胞和巨噬细胞表达多种模式识别受体（PRRs），这些受体可识别微生物结构（如核酸）中的特定病原体相关分子模式（PAMPs）。通过PRRs的信号传导导致多种细胞因子的产生，包括促炎细胞因子、干扰素（ifn）和趋化因子，以控制病毒的复制和传播。哺乳动物toll样受体（Tlrs）由十多个成员组成，是识别多种PAMPs的重要分子。西尼罗病毒（WNV）是一种可被Tlr7识别的单链RNA病毒，已在北美的人类和动物中造成严重的发病率和死亡率。我们的初步研究表明，Tlr7缺陷（Tlr7-/-）小鼠对西尼罗河病毒感染的易感性增加。此外，我们发现Tlr7-/-免疫细胞（白细胞和巨噬细胞）在大脑和肝脏中不能归家到西尼罗河病毒感染的细胞，这可能解释了为什么Tlr7-/-小鼠在西尼罗河病毒感染后死亡增加。此外，趋化因子和细胞因子阵列分析显示，Tlr7-/-小鼠巨噬细胞和血浆中IL-12/23p40 （IL-12/23p40）表达降低。此外，IL-23而非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tlr7介导的免疫细胞迁移对抗西尼罗河病毒感染的机制。特异性目的1：进一步描述WNV感染后Tlr7 -/-小鼠IL-23及其受体的表达。特异性目的2：确定IL-23-/-小鼠感染西尼罗河病毒后是否缺乏免疫细胞浸润和归巢。该项目不仅将扩大我们对Tlr7 - IL-23信号通路在西尼罗河病毒脑炎控制中的认识，而且可能产生新的治疗西尼罗河病毒感染的方法。公共卫生相关性：本项目旨在分析西尼罗病毒脑炎小鼠模型中toll样受体7介导的免疫细胞浸润和归巢对抗西尼罗病毒感染的机制。

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.