探讨补体C3a受体信号在急性肾脏感染过程中的保护作用及其机制

由大肠杆菌引起的泌尿系统感染是临床上常见问题，尽管抗生素可用于治疗,但感染反复发作以及出现抗生素耐药增多等是临床上面临的挑战。固有免疫在宿主抗感染免疫反应中发挥重要作用。补体系统是固有免疫的重要组成部分，但前期研究发现补体在肾脏感染中的作用与普遍预期矛盾。例如：大肠杆菌致病株对C5b-9介导的直接杀伤作用耐受，C5a和C3b与其相应受体作用可促进细菌入侵肾脏小管上皮细胞。目前尚不清楚补体活化是否在肾脏感染过程中也发挥保护作用。最新研究发现C3a受体信号在多种炎症、感染引起的病理损伤过程中发挥保护作用。在本项目中我们计划探讨C3a受体信号在急性肾脏感染过程中的保护作用及其机制。我们将使用受体敲除小鼠、受体激动剂以及上行性肾脏感染模型来明确C3a受体信号的保护作用，采用骨髓重构建立C3a受体嵌合小鼠以及细胞实验来探讨该过程所涉及的细胞、分子机制。我们的工作将有助于进一步认识肾脏感染的病理机制。

Urinary tract infections (UTIs) caused by uropathogenic E. coli remain among the most common infectious diseases worldwide. Despite the antimicrobial therapy, frequent recurrence or persistence of infection and increase in antibiotic resistant highlight the need for improving our understanding of the pathogenic mechanisms of this disease and developing novel treatment strategies. Innate immunity plays important roles in host defence against bacterial infection, including kidney infection. The complement system is a major component of innate immunity. However, the roles of complement in kidney infection is a paradox, for example, most human uropathogenic strains are resistant to C5b-9 mediated killing, C5a and C3b haves been suggested to have pathogenic effects through interaction with their respective receptors on tubular epithelial cells. So far, it is unclear if complement has protective effects in kidney infection. Recent studies have demonstrated that C3a exerts protective roles in several pathological conditions such as inflammation and infection through its cognate receptor C3a receptor (C3aR). In this project, we propose to investigate protective roles of C3a-C3aR signalling in acute kidney infection and the involved molecular and cellular mechanisms. We will employ a well-established murine model of ascending UTI, using C3aR knockout (KO) mice as well as C3aR agonist to determine the protective roles of C3aR in acute kidney infection. We will generate bone marrow chimeras between wildtype and C3aR KO mice to define the relative importance of C3aR on infiltrating cells in conferring the protection. We will perform a series of ex vivo and in vitro experiments to examine the effects of C3aR signalling on phagocytes, in the context of the infection (i.e. phagocytic function, apoptosis, and cytokine production). The work will describe a previously unknown roles for C3a/C3aR in pyelonephritis, provide new insight into the mechanisms of host defence against UTI and has implications for developing novel therapies for prevention and treatment of this disease.