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

TLR7介导免疫细胞浸润和归巢以对抗西尼罗河病毒感染

• 批准号: 7924032
• 负责人: FENGWEI BAI
• 金额: $ 9.13万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924032
• 关键词: American; Animals; Antigen-Presenting Cells; Brain; Cells; Cessation of life; Dendritic Cells; Development; Encephalitis; Endosomes; Flow Cytometry; Goals; Home environment; Homing; Host Defense; Human; ITGAM gene; Immune; In Vitro; Infiltration; Interferons; Interleukin-12; Invaded; Leukocytes; Ligands; Liver; Loxoribine; Mammalian Cell; Measures; Mediating; Microglia; Microscope; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Immunity; North America; Nucleic Acids; PTPRC gene; Pattern; Pattern recognition receptor; Plasma; Predisposition; Production; RNA Viruses; Residual state; Signal Pathway; Signal Transduction; Structure; T-Lymphocyte; TLR7 gene; Toll-like receptors; Viral; Virus; Virus Diseases; West Nile virus; Western Blotting; Wild Type Mouse; Work; cell motility; chemokine; combat; cytokine; human TLR7 protein; in vivo; interleukin-12 subunit p35; interleukin-23; macrophage; member; microbial; migration; mortality; novel therapeutics; pathogen; public health relevance; receptor

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.

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。在宿主体内，抗原呈递细胞（例如树突状细胞和巨噬细胞）表达多种模式识别受体（PRR），这些受体可识别微生物结构（例如核酸）内的特定病原体相关分子模式（PAMP）。通过 PRR 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，以控制病毒复制和传播。哺乳动物 Toll 样受体 (Tlrs) 由十多个成员组成，对于识别多种 PAMP 非常有用。西尼罗河病毒（WNV）是一种可被 Tlr7 识别的单链 RNA 病毒，在北美造成人类和动物严重发病和死亡。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）无法归巢于大脑和肝脏中受 WNV 感染的细胞，这可能解释了为什么 Tlr7-/- 小鼠在感染 WNV 后死亡率增加。此外，趋化因子和细胞因子阵列分析表明，Tlr7-/-小鼠的巨噬细胞和血浆中白介素-12/23p40（IL-12/23p40）表达降低。此外，发现IL-23而非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。具体目标1：进一步研究WNV感染后Tlr7 -/- 小鼠中IL-23及其受体的表达。具体目标 2：确定 IL-23-/- 小鼠在感染 WNV 后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 信号通路控制西尼罗河病毒脑炎的认识，而且可能会产生针对西尼罗河病毒感染的新疗法。公共健康相关性：该项目旨在剖析 Toll 样受体 7 介导的免疫细胞浸润和归巢的机制，以在西尼罗河病毒脑炎小鼠模型中对抗西尼罗河病毒感染。