Complement Anaphylatoxin Receptors in Inflammation and Immunity

描述（由申请人提供）：感染革兰氏阳性细菌单核增生李斯特菌（Lm）后，先天免疫反应被迅速触发，对宿主生存至关重要。尽管先天免疫系统在对抗Lm感染中很重要，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是过敏性疾病（包括哮喘）中t细胞效应功能的有效调节剂。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然未知。此外，对于过敏毒素如何影响宿主清除细胞内细菌（如Lm）所必需的CD8+ t细胞反应，人们知之甚少。本研究计划的长期目标是描述先天和适应性免疫反应中补体过敏毒素介导的重要生物学途径，以便制定适当的治疗策略，消除C3a和C5a的有害高炎症作用，同时不损害宿主对传染病的免疫反应。这些研究是由一个中心假设驱动的，即过敏毒素结合其特异性受体介导许多生物学功能，这些功能对于强大的先天和适应性免疫应答所需的途径的启动、延续和调节至关重要。还有一种假设认为，这些极其有效的炎症分子的急性或慢性释放可能导致的有害和潜在致命影响，是由特定的羧基肽酶（CPN和TAFI）和假定的“诱饵”受体C5L2R在系统和局部进行调节的。中心假设将在目前的应用中通过两个主要的特定目标进行验证，这些目标将在系统性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过敏毒素及其特异性受体（分别为C3aR和C5aR）在Lm感染反应中调节先天免疫和适应性免疫的细胞和分子机制。目的2将描述羧基肽酶（CPN和TAFI）调节和C5L2R结合如何影响过敏毒素对Lm感染的先天和适应性免疫的调节。提出的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毒素介导的众多先天和t细胞免疫调节途径。此外，这些研究的数据将为补体在宿主对Lm（一种重要的NIAID B类细胞内病原体）的应答中所起的作用提供新的重要数据。

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.