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: 7739188
• 负责人: FENGWEI BAI
• 金额: $ 9.11万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739188
• 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的第一行，以防止包括病毒在内的入侵病原体。在宿主中，抗原呈递细胞（例如树突状细胞和巨噬细胞）表达了多种模式识别受体（PRR），这些受体识别微生物结构（例如核酸）内的特定病原体相关的分子模式（PAMP）。通过PRRS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，以控制病毒复制和扩散。由十多个成员组成的哺乳动物收费受体（TLR）对于识别多种弹药的策略是策划的。西尼罗河病毒（WNV）在北美引起了人类和动物的严重发病率和死亡率，是一种单链RNA病毒，可以被TLR7识别。我们的初步研究表明，TLR7缺乏（TLR7 - / - ）小鼠会增加对WNV感染的敏感性。此外，我们发现TLR7 - / - 免疫细胞（白细胞和巨噬细胞）未能进入大脑和肝脏中WNV感染的细胞，这可能解释了为什么TLR7 - / - 小鼠会增加WNV感染后死亡的死亡。此外，趋化因子和细胞因子阵列分析表明，在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而不是IL-12可以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的机制，以打击WNV感染。具体目标1：在WNV感染后，进一步描绘了IL-23及其受体在TLR7 - / - 小鼠中的表达。具体目标2：确定IL-23 - / - 小鼠是否缺乏WNV感染后免疫细胞浸润和归巢。该项目不仅会扩展我们对WNV脑炎控制TLR7 -IL -23信号通路的理解，而且可能导致针对WNV感染的新疗法。公共卫生相关性：该项目旨在剖析类似Toll样受体的机制7-介导的免疫细胞浸润和归巢，以抵抗西尼罗河病毒脑炎的鼠模型中西尼罗河病毒感染。