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

描述(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入侵病原体的第一道防线。在宿主内部，抗原提呈细胞，如树突状细胞和巨噬细胞，表达各种模式识别受体(PRRs)，识别核酸等微生物结构中特定的病原体相关分子模式(PAMPs)。通过PRRs信号传递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。哺乳动物的Toll样受体(Toll-like Receptor，TLRs)由十多个成员组成，是识别多种PAMP的关键分子。西尼罗河病毒(West Nile Virus，WNV)是一种可被TLR7识别的单链RNA病毒，曾在北美造成人和动物的严重发病和死亡。我们的初步研究表明，TLR7缺陷(TLR7-/-)小鼠增加了对WNV感染的易感性。此外，我们发现TLR7-/-免疫细胞(白细胞和巨噬细胞)不能在脑和肝脏中定位于WNV感染细胞，这可能解释了为什么TLR7-/-小鼠在WNV感染时增加死亡。此外，趋化因子和细胞因子阵列分析显示，IL-12/23p40(IL-12/23p40)在TLR7-/-小鼠的巨噬细胞和血浆中的表达降低。此外，IL-23而不是IL-12能够在体外吸引野生型巨噬细胞迁移。在这个拟议的项目中，我们将剖析TLR7介导的免疫细胞迁移以对抗西尼罗河病毒感染的潜在机制。具体目的1：进一步研究WNV感染TLR7-/-小鼠后IL-23及其受体的表达。具体目的2：确定WNV感染后IL-23-/-小鼠是否存在免疫细胞浸润和归巢缺陷。该项目不仅将扩大我们对TLR7-IL-23信号通路在控制WNV脑炎中的认识，而且可能会导致针对WNV感染的新的治疗方法。公共卫生相关性：本项目旨在剖析Toll样受体7介导的免疫细胞渗透和归巢在西尼罗河病毒脑炎小鼠模型中对抗西尼罗河病毒感染的机制。

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.