The Role of Negative Signal in Early Infection

描述(由申请人提供)：已知共刺激和共抑制信号在感染反应的后期或收缩阶段是必不可少的，特别集中在获得性免疫上。然而，它们在早期对急性感染的先天免疫中的作用还知之甚少。这项应用的长期目标是阐明正负信号网络调节感染免疫反应早期阶段的机制。本研究的重点是配体HVEM和BTLA。我们的初步数据显示，在感染的最初几天，BTLA信号抑制了细菌的清除，并且这种作用依赖于CD8+T细胞。因此，我们假设，HVEM通过BTLA微调早期的先天免疫反应来传递负面信号，以减少免疫病理并提供强大的抗细菌反应。本项目的具体目标是：1)确定T细胞上BTLA信号抑制炎性先天反应的机制；2)阐明T细胞上BTLA信号调节先天免疫抗感染的机制。这项研究有望对人类健康产生重大的积极影响，因为它将增加我们对抗细菌免疫反应及其相关免疫病理学能力的了解，并将为如何设计新的更好的治疗方法来对抗感染和限制病理提供线索。急性感染的死亡率和发病率很高，这是因为在免疫反应的早期阶段，发挥作用的系统被强烈激活。然而，调节这一免疫反应早期阶段的机制还没有很好地确定。本研究将探讨HVEM分子对早期免疫反应的刺激和抑制调节，并将指导新的治疗方法，以增强感染的清除，同时限制对宿主的负面影响。 公共卫生相关性：急性感染具有很高的死亡率和发病率，因为在免疫反应的早期阶段发挥作用的系统被强烈激活，但尚不清楚免疫反应在早期急性阶段是否以及如何受到负面调节。这项研究将确定宿主对急性感染的免疫反应是否以及如何受到负调控；这些机制可能对免疫和免疫介导的损伤之间的平衡至关重要。

DESCRIPTION (provided by applicant): Co-stimulatory and co-inhibitory signaling is known to be essential at the late, or contracting, stage of the response to infection, concentrating specifically on adaptive immunity. However, their roles in the early, innate-mediated immunity to acute infection are poorly understood. The long-term goal of this application is to elucidate the mechanisms by which positive and negative signaling networks regulate the early phase of the immune response to infection. This study will focus on the ligand HVEM and BTLA. Our preliminary data show that during the first few days of infection, BTLA signaling suppresses bacterial clearance, and that this effect is dependent on CD8+ T cells. We hypothesize, therefore, that HVEM delivers a negative signal through BTLA fine-tuning the early, innate immune response to reduce immunopathology and provide a robust anti-bacterial response. The specific aims of this project are 1) to determine the mechanisms by which BTLA signaling on T cells acts to limit the inflammatory innate response, and 2) to elucidate the mechanisms by which BTLA signaling on T cells regulates innate immunity against infection. This study is expected to have significant positive effects on human health as it will increase our knowledge of the anti-bacterial immune response and its associated capacity for immunopathology, and will provide clues for how to design new and better therapies to combat infection and limit pathology. Acute infection has high mortality and morbidity due to the strong activation of the systems at play in the early phase of the immune response. However, the mechanisms for regulating this early phase of the immune response are not well defined. This study will probe both the stimulatory and inhibitory regulation of the early immune response by the molecule HVEM, and will guide new treatments to enhance the clearance of infection while limiting negative effects to the host. PUBLIC HEALTH RELEVANCE: Acute infection has high mortality and morbidity due to strong activation of the systems at play in the early phase of the immune response but it is unclear whether and how the immune response is negatively regulated during the early acute phase. This study will define whether and how host immune responses against acute infection are under negative regulation; these mechanisms may be important for the balance between immunity an immune-mediated injury.