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: 8675533
• 负责人: Mehul Shamal Suthar
• 金额: $ 51.58万
• 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/8675533
• 关键词: Adaptor Signaling Protein; Antiviral Agents; 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 virus; Work; adaptive 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的目标是了解在黄病毒感染期间先天免疫感知和保护性T细胞免疫反应调节之间的串扰。西尼罗河病毒(WNV)和日本脑炎病毒(JEV)是由蚊媒传播的新出现的黄病毒，在全球范围内引起病毒性脑炎的年度流行。目前还没有被批准用于人类治疗西尼罗河病毒感染的疫苗或疗法，目前预防乙脑病毒感染的疫苗也不能提供终身保护性免疫。对西尼罗河病毒和乙脑病毒的保护是由先天免疫反应和获得性免疫反应介导的。RLG-1样受体(RLR)是一种胞质病原体识别受体，识别非自身RNA，并通过MAVS接头蛋白发出信号，触发对西尼罗河病毒和乙脑病毒的先天抗病毒免疫。除了在先天性免疫中的作用外，我们的实验室最近发现，RLR途径的组成部分对于编程保护性适应性免疫反应至关重要，这些免疫反应负责在感染的后期清除病毒。这包括MAVS介导的体液和细胞免疫反应(CD8+、CD4+和Treg反应)的调节，以及在西尼罗河病毒感染过程中LGP2介导的T细胞免疫调节。LGP2被发现以细胞固有的方式发挥作用，控制CD8+T细胞的存活和效应器特性。这些发现证实，在黄病毒感染期间，RLRs调节先天免疫和获得性免疫之间的界面。然而，RLR调节T细胞免疫对抗黄病毒感染和疫苗接种的免疫学机制尚不清楚。项目4的研究将(1)确定RLR信号和功能在调节T细胞启动中的作用；(2)确定MAV和LGP2在调节效应器和记忆性T细胞反应中的T细胞固有功能；(3)确定MAV和LGP2如何调节记忆性T细胞回忆反应。这项工作将揭示免疫记忆的先天免疫调节的新见解，并确定针对黄病毒感染的疫苗保护的新治疗靶点和策略。