肠道中梭杆菌的菌种结构多样性及其保守外膜蛋白BamA致病机制研究

肠道菌群中梭杆菌参与肠道疾病发生发展。但肠道梭杆菌的菌种结构特征、毒力因子和致病机制尚不明确。本课题发现肠道梭杆菌有菌种多样性，结构组成在个体间存在差异；但不同梭杆菌菌种反而表现类似毒力，提示它们可能具有共同毒力因子；进而经比较基因组学发现参与V型分泌的BamA蛋白在梭杆菌中保守，有潜在毒力功能。我们推测：BamA为梭杆菌共有毒力因子，通过控制其他毒力因子分泌或/和通过与宿主细胞直接作用，介导肠道梭杆菌发挥致病性。我们将通过bamA基因敲除回补、细胞动物实验、效应物鉴定、蛋白结构鉴定、生物信息学挖掘、临床样本分析等，研究：（1）梭杆菌保守蛋白BamA介导的毒力及与宿主细胞互作机制，（2）BamA介导毒力效应物释放机制及与效应物间间调控作用；（3）BamA生物学功能的结构基础。阐明BamA参与梭杆菌致病性的分子机制；探索梭杆菌促进肠道疾病发生发展的病因学，为相关疾病诊疗提供新思路。

The Fusobacterium in gut microbiota has been proven to involve in the pathogenesis of certain intestinal diseases. But the composition features of gut Fusobacterium communities, the virulence factors encoded by this genus and the relevant pathogenic mechanisms are largely unknown. This project has discovered that the species compositions of gut Fusobacterium communities display diversity and there also is composition variety among hosts. But interestingly, isolates of different species showed similar virulence, suggesting that Fusobacterium may encode conserved virulence factors. Further comparative genomic analysis revealed that an outer membrane protein, BamA, recently found to be responsible for type V secretion, was conserved among Fusobacterium and might participate in virulence. We hypothesize that BamA is a conserved virulence factor of Fusobacterium via controlling the secretion of other virulence effectors and/or direct interaction with host cells in gut. We will conduct bamA gene knockout and complementation, cellular and animal study, effector characterization, protein structure characterization, bioinformatics and clinical study, to investigate a) the virulence and the relevant molecular change in host cells mediated by BamA; b) virulence effector secretion mechanism of BamA and its regulation on effectors; and c) the structural basis of BamA. This project will illustrate the molecular mechanism of BamA-mediated virulence of Fusobacterium, which could promote the understanding of Fusobacterium-driven etiology of gut diseases and provide new thoughts to the diagnosis and treatment of gut diseases.