Project 4, RIG-1-like receptor regulation of T cell immunity against flavivirus

项目4、RIG-1样受体调节T细胞抗黄病毒免疫

• 批准号: 9067906
• 负责人: Mehul Shamal Suthar
• 金额: $ 50.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9067906
• 关键词: Adaptor Signaling Protein; CD8B1 gene; Cell Survival; Cells; Collaborations; Critical Pathways; Culicidae; Diamond; Encephalitis; Epidemic; Flavivirus; Flavivirus Infections; Generations; Goals; Human; Immune; Immune response; Immunity; Immunologic Memory; Infection; Japanese encephalitis virus; Knockout Mice; Knowledge; Laboratories; Life; Mediating; Memory; Mosquito-Borne Encephalitis; Mus; Natural Immunity; Production; Property; RNA; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Resources; Role; Signal Transduction; Staging; T cell regulation; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Vaccination; Vaccines; Virus; Virus Diseases; West Nile viral infection; West Nile virus; Work; adaptive immunity; antiviral immunity; biological systems; cell mediated immune response; cytokine; cytosolic receptor; insight; memory recall; new therapeutic target; novel; pathogen; prevent; programs; receptor; response

The goal of Project 4 is to understand the crosstalk between innate immune sensing and regulation of protective T cell immune response during flavivirus infection. West Nile virus (WNV) and Japanese encephalitis virus (JEV) are emerging mosquito-borne flaviviruses that globally cause annual epidemics of virus-induced encephalitis. T here is no approved vaccine or therapy for use in humans to treat WNV infection and the current vaccines to prevent JEV infection do not provide life-long protective immunity. Protection against WNV and JEV is mediated by both innate and adaptive immune responses. The RlG-1 like receptors (RLR) are cytosolic pathogen recognition receptors that recognize non-self RNA and signal through the MAVS adaptor protein to trigger innate antiviral immunity against WNV and JEV. In addition to their role in innate immunity, our laboratory recently discovered that components of the RLR pathway are critical for programming protective adaptive immune responses responsible for clearing virus during the later stages of infection. This includes MAVS-mediated regulation of humoral and cell-mediated immune responses (CD8+, CD4+ and Treg responses) as well as LGP2-mediated regulation of T cell immunity during WNV infection. LGP2 was found to function in a cell-intrinsic manner to control CD8+ T cell survival and effector properties. These findings establish that the RLRs regulate the interface between innate and adaptive immunity during flavivirus infection. However, the immunological mechanism underlying RLR regulation of T cell immunity against flavivirus infection and vaccination are not well understood. Project 4 studies will (1) determine the role of RLR signaling and function in regulating T cell priming; (2) define the Tcell intrinsic function of MAVS and LGP2 in regulating effector and memory T cell responses; (3) determine how MAVS and LGP2 function to regulate memory T cell recall responses. This work will reveal novel insights into innate immune regulation of immunological memory and identify new therapeutic targets and strategies for vaccine protection against flavivirus infection.

项目4的目标是了解黄病毒感染期间先天免疫感知和保护性T细胞免疫应答调节之间的串扰。西尼罗河病毒（WNV）和日本脑炎病毒（JEV）是新出现的蚊媒黄病毒，在全球范围内引起病毒诱导的脑炎的年度流行。目前还没有批准的疫苗或治疗方法用于人类治疗WNV感染，目前预防JEV感染的疫苗不能提供终身保护性免疫。对WNV和JEV的保护是由先天性和适应性免疫应答介导的。RlG-1样受体（RLR）是胞质病原体识别受体，其识别非自身RNA并通过MAVS衔接蛋白发出信号以触发针对WNV和JEV的先天性抗病毒免疫。除了它们在先天免疫中的作用外，我们的实验室最近发现，RLR途径的组分对于编程保护性适应性免疫应答至关重要，这些免疫应答负责在感染后期清除病毒。这包括在WNV感染期间MAVS介导的体液和细胞介导的免疫应答（CD 8+、CD 4+和Treg应答）的调节以及LGP 2介导的T细胞免疫的调节。发现LGP 2以细胞内在方式起作用以控制CD 8 + T细胞存活和效应子特性。这些发现证实了在黄病毒感染期间，RLR调节先天免疫和适应性免疫之间的界面。然而，RLR调节T细胞免疫抵抗黄病毒感染和疫苗接种的免疫学机制还不清楚。项目4研究将（1）确定RLR信号传导和功能在调节T细胞引发中的作用;（2）确定MAVS和LGP 2在调节效应和记忆T细胞应答中的T细胞内在功能;（3）确定MAVS和LGP 2如何发挥作用以调节记忆T细胞回忆应答。这项工作将揭示免疫记忆的先天免疫调节的新见解，并确定新的治疗靶点和疫苗保护黄病毒感染的策略。