HVEM-BTLA system in Inflammation

描述（由申请人提供）：项目总结有效的宿主防御病毒病原体需要抗原受体活化和来自细胞表面分子和细胞因子的协同信号（共信号）。疱疹病毒进入介体（HVEM; TNFRSF 14）是TNF受体超家族的成员，作为由辅助受体LIGHT（TNFSF 14）和免疫球蛋白超家族成员BTLA（B和T淋巴细胞衰减剂）启动的促炎性和抑制性辅助信号通路之间的分子开关。新的结果表明，有效的记忆T细胞分化需要HVEM共信号系统，然而，病毒病原体篡夺HVEM途径，以阻挠有效的宿主防御。本项目的重点是HVEM系统在病毒潜伏期。我们最近发现，单纯疱疹病毒（HSV）-1需要LIGHT-HVEM-BTLA系统来维持小鼠眼部感染模型中三叉神经节中的潜伏期。我们的初步证据表明HSV-1不能有效地维持HVEM、BTLA或LIGHT遗传缺陷的小鼠的潜伏期，并且病毒潜伏期相关转录物（LAT）独特地上调潜伏感染神经节中的HVEM表达。此外，在缺乏HVEM或LAT缺陷的HSV的小鼠中，在潜伏感染期间效应T细胞未能在神经节中积累。这些结果暗示了HVEM共信号通路在HSV-1感染的神经元和效应T细胞控制潜伏期中的多种作用。我们已经招募了关键的合作者，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的目标：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作用的分子相互作用，以及2）研究HVEM信号传导在潜伏期的神经元和淋巴区室中的体内需求。本研究将为HVEM共信号系统调控病毒致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.