Complement Anaphylatoxin Receptors in Inflammation and Immunity

描述（由申请方提供）：感染革兰氏阳性细菌单核细胞增生李斯特菌（Lm）后，先天免疫应答迅速触发，对宿主存活至关重要。尽管先天免疫系统在对抗Lm感染中的重要性，但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细胞对细菌病原体应答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胞内细菌（如Lm）所必需的CD8 + T细胞应答，了解甚少。该研究项目的长期目标是描述先天性和适应性免疫应答中补体过敏毒素介导的重要生物学途径，以便开发适当的治疗策略，消除C3a和C5a的有害的过度炎症作用，而不损害宿主对感染性疾病的免疫应答。这些研究是由中心假设驱动的，即过敏毒素结合其特异性受体介导许多生物学功能，这些功能对于启动、维持和调节强大的先天性和适应性免疫应答所需的途径至关重要。还假设，由这些极其有效的炎性分子的急性或慢性释放引起的有害和潜在的致死作用由特异性羧肽酶（CPN & TAFI）和推定的"诱饵"受体C5L2R全身和局部调节。在本申请中，将通过两个主要的具体目标来检验中心假设，这两个主要的具体目标将在全身性Lm感染模型中采用C3aR、C5aR、C5L2R和羧肽酶KO小鼠的新组合。目的1将阐明C3a和C5a过敏毒素及其特异性受体（分别为C3aR和C5aR）调节Lm感染应答的先天性和获得性免疫的细胞和分子机制。目的2将描述羧肽酶（CPN & TAFI）调节和C5L2R结合如何影响过敏毒素对先天性和适应性免疫的调节。拟议的研究提供了一个独特的和强大的体内系统，全面描绘了许多先天性和T细胞免疫调节途径，是由补体过敏毒素介导的。此外，来自所提出的研究的数据将提供关于补体在宿主对Lm（一种重要的NIAID类别B优先胞内病原体）的应答中的作用的新的和重要的数据。

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.