HVEM-BTLA system in Inflammation

项目概述：有效的宿主防御病毒病原体需要抗原受体激活和细胞表面分子和细胞因子的协同信号传导。疱疹病毒进入介质（HVEM; TNFRSF14）是TNF受体超家族的一员，在由辅助受体LIGHT （TNFSF14）和免疫球蛋白超家族成员BTLA （B和T淋巴细胞衰减剂）启动的促炎和抑制性共信号通路之间起分子开关作用。新的研究结果表明，有效的记忆T细胞分化需要HVEM共信号系统，然而，病毒病原体篡占HVEM途径来阻止有效的宿主防御。本项目主要研究病毒潜伏期中的HVEM系统。我们最近在小鼠眼部感染模型中发现单纯疱疹病毒(HSV)-1需要LIGHT-HVEM-BTLA系统维持三叉神经节的潜伏期。我们的初步证据表明，HSV-1不能有效地维持HVEM、BTLA或LIGHT基因缺陷小鼠的潜伏期，病毒潜伏期相关转录物（LAT）在潜伏感染的神经节中独特地上调HVEM的表达。此外，在缺乏HVEM或缺乏LAT的HSV小鼠的潜伏感染期间，效应T细胞不能在神经节中积聚。这些结果暗示了HVEM共信号通路在HSV-1感染的神经元和控制潜伏期的效应T细胞中的多重作用。我们招募了重要的合作者，并开发了动物和组织培养模型，可以使用遗传和生化方法来研究病毒潜伏期中的HVEM共信号通路。为了实现这一目标，我们提出了两个具体目标：1)表征调节HVEM及其配体在神经元和T细胞系中的表达和共信号传导作用的分子相互作用；2)研究潜伏期神经元和淋巴细胞室中HVEM信号传导的体内需求。这项研究将为HVEM共信号系统调控病毒发病机制提供新的见解。

DESCRIPTION (provided by applicant): PROJECT SUMMARY Effective host defense against viral pathogens requires antigen-receptor activation and cooperating signaling (cosignaling) from cell surface molecules and cytokines. The herpesvirus entry mediator (HVEM; TNFRSF14), a member of the TNF Receptor superfamily, serves as a molecular switch between proinflammatory and inhibitory cosignaling pathways initiated by coreceptors, LIGHT (TNFSF14) and the immunoglobulin superfamily member BTLA (B and T lymphocyte attenuator). New results indicate effective memory T cell differentiation requires the HVEM cosignaling system, however, viral pathogens usurp the HVEM pathway to thwart effective host defense. This project focuses on the HVEM system in viral latency. We recently discovered that Herpes Simplex virus (HSV)-1 requires LIGHT-HVEM-BTLA system to maintain latency in the trigeminal ganglia in a mouse ocular infection model. Our preliminary evidence indicates that HSV-1 is unable to efficiently maintain latency in mice genetically deficient in HVEM, BTLA or LIGHT and the viral latency- associated transcript (LAT) uniquely upregulates HVEM expression in latently infected ganglia. Moreover, effector T cells fail to accumulate in the ganglia during latent infection in mice lacking HVEM or HSV deficient in LAT. These results implicate multiple roles for the HVEM cosignaling pathway in HSV-1 infected neurons and in effector T cells controlling latency. We have recruited key collaborators and developed animal and tissue culture models that can be probed using genetic and biochemical approaches to investigate the HVEM cosignaling pathway in viral latency. To accomplish this goal we propose two specific aims: 1) characterize molecular interactions regulating the expression and cosignaling actions of HVEM and its ligands in neuronal and T cell lines, and 2) investigate the requirement of HVEM signaling in vivo in neuronal and lymphoid compartments in latency. This investigation will provide new insight into the mechanisms of the HVEM cosignaling system in regulating viral pathogenesis.