Complement Anaphylatoxin Receptors in Inflammation and Immunity

描述(由申请人提供)：在感染革兰氏阳性细菌单核细胞增生性李斯特菌(Lm)后，先天免疫反应被迅速触发，对宿主的生存至关重要。尽管先天性免疫系统在对抗LM感染方面很重要，但人们对补体的作用知之甚少。现在有强有力的证据表明，补体过敏毒素C3a和C5a在包括哮喘在内的过敏性疾病中是T细胞效应器功能的有效调节器。然而，C3a/C5a调节T细胞对细菌病原体反应的生物学相关性在很大程度上仍不清楚。此外，对过敏毒素如何影响CD8+T细胞反应的了解很少，CD8+T细胞反应是宿主清除细胞内细菌(如LM)所必需的。该研究计划的长期目标是描述补体过敏性毒素在先天性和获得性免疫反应中介导的重要生物学途径，以便开发适当的治疗策略，在不损害宿主对传染病的免疫反应的情况下消除C3a和C5a的有害的高炎症效应。这些研究是由一个中心假设推动的，即与其特定受体结合的过敏性毒素介导了许多生物学功能，这些功能对于强健的先天免疫反应和获得性免疫反应所需的途径的启动、持续和调节至关重要。它还假设，这些极其有效的炎症分子的急性或长期释放所产生的有害和潜在的致命影响，在系统和局部都受到特定的羧基肽酶(CPN和TAFI)和假定的“诱饵”受体C5L2R的调节。在目前的应用中，将通过两个主要的具体目标来检验中心假设，这两个主要目标将在系统性LM感染模型中使用C3aR、C5aR、C5L2R和羧肽酶KO小鼠的新组合。目的1将描述C3a和C5a过敏性毒素及其特异性受体(分别为C3aR和C5aR)调节先天性免疫和获得性免疫应答的细胞和分子机制。目的2阐明Cpn&TAFI调节和C5L2R结合如何影响金黄色葡萄球菌感染后天然和获得性免疫应答中的过敏性毒素调节。这项研究提供了一个独特而强大的体内系统来全面描述补体过敏性毒素介导的众多天然和T细胞免疫调节通路。此外，来自拟议研究的数据将提供新的和重要的数据，关于补体在宿主对LM的反应中的作用，LM是一种重要的NIAID B类优先细胞内病原体。

DESCRIPTION (provided by applicant): Following infection with the gram positive bacterium Listeria monocytogenes (Lm), innate immune responses are rapidly triggered and are essential for host survival. Despite the importance of the innate immune system in fighting an Lm infection, little is known about the role of complement. There is now strong evidence that the complement anaphylatoxins, C3a and C5a, are potent modulators of T-cell effector functions in allergic diseases, including asthma. However, the biological relevance of C3a/C5a modulation of T-cell responses to bacterial pathogens remains largely unknown. In addition, there is very little understanding of how the anaphylatoxins impact CD8+ T-cell responses that are essential for host clearance of intracellular bacteria such as Lm. The long term goal of this research program is to delineate important biological pathways mediated by the complement anaphylatoxins in innate and adaptive immune responses so that appropriate therapeutic strategies can be developed that will abrogate the deleterious hyper-inflammatory effects of C3a and C5a without impairing the host immune response to infectious disease. These studies are driven by the central hypothesis that the anaphylatoxins on binding their specific receptors mediate numerous biological functions that are critical for the initiation, perpetuation, and regulation of pathways required for robust innate as well as adaptive immune responses. It is also hypothesized that the deleterious and potentially lethal effects that can result from the acute or chronic release of these extremely potent phlogistic molecules are regulated both systemically and locally by specific carboxypeptidases (CPN & TAFI) and by the putative "decoy" receptor C5L2R. The central hypothesis will be tested in the current application by two major specific aims that will employ novel combinations of C3aR, C5aR, C5L2R, and carboxypeptidase KO mice in a model of systemic Lm infection. Aim 1 will delineate cellular and molecular mechanisms by which the C3a and C5a anaphylatoxins and their specific receptors (C3aR and C5aR, respectively) modulate innate and adaptive immunity in response to Lm infection. Aim 2 will delineate how carboxypeptidase (CPN & TAFI) regulation and C5L2R binding impact anaphylatoxin modulation of innate and adaptive immunity in response to Lm infection. The proposed research provides a unique and powerful in vivo system to delineate comprehensively numerous innate and T-cell immunomodulatory pathways that are mediated by the complement anaphylatoxins. Moreover, the data from the proposed studies will provide novel and important data regarding complement's role in the host response to Lm, an important NIAID category B priority intracellular pathogen.