HVEM-BTLA system in Inflammation

描述(由申请人提供)：针对病毒病原体的有效宿主防御需要抗原受体激活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(HTEM；TNFRSF14)是肿瘤坏死因子受体超家族的成员之一，是由辅受体LIGH(TNFSF14)和免疫球蛋白超家族成员BTLA(B和T淋巴细胞衰减器)启动的促炎和抑制共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。我们最近发现，单纯疱疹病毒(HSV)-1需要LIGH-HBEM-BTLA系统来维持小鼠眼部感染模型中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LIGH基因缺陷小鼠的潜伏期，并且病毒潜伏期相关转录本(LAT)独特地上调潜伏期感染神经节中HVEM的表达。此外，在LAT缺乏HVEM或HSV的小鼠的潜伏感染期间，效应性T细胞无法在神经节中积聚。这些结果暗示在HSV-1感染的神经元和控制潜伏期的效应器T细胞中，HVEM共信号通路具有多重作用。我们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探索病毒潜伏期中的HVEM共信号通路。为了实现这一目标，我们提出了两个特定的目标：1)表征在神经元和T细胞系中调节HVEM及其配体的表达和共信号作用的分子相互作用；2)研究在体内神经元和淋巴细胞室对HVEM信号潜伏期的需求。这一研究将为病毒协同信号系统调控病毒致病的机制提供新的见解。

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.