肺炎链球菌肽链内切酶O(PepO)增强巨噬细胞吞噬功能的分子机制研究

Virulence factors are of importance in making bacteria morbigenous. Insights into the molecular mechanisms of the interaction between them and the host may provide new choices for the prevention and treatment of bacterial infection. Steptococcus pneumoniae endopeptidase O(PepO) is a newer discovered and extensively expressed pneumococcal virulence protein. Our previous work demonstrated that PepO enhanced the phagocytosis by macrophages in a TLR2 and miR-155 dependent manner. However, the precise molecular mechanisms are still unclear, further research is still needed. In this proposal we will deeply explore the underlying mechanisms through investigating the role of SHIP1 and CR3 in modulating the PepO-induced phagocytosis by macrophages. This project will provide novel insights for the prevention and treatment of pneumococcal diseases, also lay the basis for the development of new protein vaccine and antibiotic drugs.

毒力因子是细菌致病的关键因子，深入研究其与宿主相互作用的分子机制可能为防治细菌感染提供新的选择。肺炎链球菌肽链内切酶O（PepO）是一种新近发现的在肺炎链球菌不同荚膜血清型菌株中保守表达的毒力蛋白。课题组前期研究发现，PepO能诱导巨噬细胞吞噬功能的增强，且这一效应依赖于TLR2、miR-155。但确切的分子机制仍不清楚。本课题围绕PepO增强巨噬细胞的吞噬功能这一主线，以SHIP1、CR3为切入点，深入探索PepO发挥该效应的分子机制，为防治肺炎链球菌感染寻求新的理论突破，同时为以PepO 为靶点研发新的抗菌药物及蛋白疫苗提供有价值的理论依据。

新发感染的大流行、已控制的感染性疾病重新流行以及抗生素耐药菌株的不断增加，使感染性疾病成为人类健康的最大威胁。临床上亟需新的、有效的手段来预防和治疗感染性疾病。越来越多的证据表明，一些微生物制剂和微生物产物可通过包括免疫调节在内的多种机制来保护机体免受细菌和病毒等病原体的侵害。本项目以肺炎链球菌保守毒力蛋白肽链内切酶O（PepO）为研究对象，深入探索其免疫调节效应及发挥该效应的分子机制。研究结果显示PepO一方面通过TLR2受体抑制SHIP1的表达，从而上调CR3的表达增强巨噬细胞的吞噬功能。另一方面通过TLR2和TLR4受体抑制PI3K/Akt/mTOR、激活AMPK/ULK-1信号通路诱导细胞自噬增强巨噬细胞的吞噬和杀菌功能。动物实验结果显示PepO可促进小鼠对鼻咽部及肺部常见致病菌肺炎链球菌、金黄色葡萄球菌和铜绿假单胞菌的清除，且该效应依赖于其对巨噬细胞的免疫调节作用。综上，本项目研究为呼吸道感染性疾病提供了一种新的预防和治疗措施，并为开发以PepO为靶点的免疫调节剂提供了有价值的实验依据。