鲍曼不动杆菌种优势性：不动杆菌属不同菌种生存、毒力与耐药性比较研究

The genus Acinetobacter is commonly regarded as an environmental organism which is not associated with human disease. But its most clinically relevant species, A. baumannii, has emerged as one of the most troublesome pathogens for nosocomial infections in the past decades. Survival and persistence, virulence, and resistance to antimicrobial agents lead to the worldwide spread and the difficulty of clinical therapy of A. baumannii infection. In this proposal, we plan to examine the selected strains representing distinct species or clones in order to evaluate the survival or persistence ability on hostile environment and their metabolic activity. The adherence, cell apoptosis, inflammatory cytokine induction, biofilm formation of different Acinetobacter species will also be compared, and their pathogenicity to Galleria mellonella will be determined. The in vivo negative selection in transposon mutants library will be employed for screening novel virulence factors. We will also search the Acinetobacter spp. chromosome and plasmid nucleotide sequence to find the horizontal transfer elements, explore the evolution and transfer mechanism of OXA-type carbapenemase gene, investigate the drug efflux pump, and search for new resistance islands and new resistance genes. Comparison of A. baumannii and other Acinetobacter species can explain the species advantage of A. baumannii in survival and persistence, virulence, drug resistance and causing nosocomial infections, transmission and epidemic spread in healthcare institutions. We hope to find the control method and therapy strategy for this clinical pathogen.

不动杆菌属细菌常见于环境中，对人致病力普遍较弱，但鲍曼不动杆菌在短短二三十年迅速成为医院感染重要病原菌，其生存能力、毒力和耐药水平相对于其它不动杆菌属菌种存在明显优势，造成世界范围的广泛流行，临床治疗非常困难。本研究挑选代表不同种或不同克隆型的不动杆菌属菌株，评估它们在逆境中的生存能力、营养的代谢能力及其与基因组背景的联系；比较对细胞的粘附、引起细胞凋亡、诱导炎症因子、形成生物被膜等致病能力以及对大蜡螟幼虫的毒力差异，突变体库负筛选新的毒力因子；筛查不动杆菌基因组中外来移动元件和质粒结构，探索以OXA型碳青霉烯酶基因为代表的耐药基因进化及水平转移机制，明确和耐药相关的外排系统，探寻并验证新耐药岛和新耐药基因。对鲍曼不动杆菌与其它不动杆菌的比较可以帮助了解鲍曼不动杆菌在生存能力、毒力与耐药方面的种优势性，揭示其在临床环境中广泛传播的原因，为进一步寻求控制策略和指导临床治疗提供基础。

鲍曼不动杆菌近年来成为医院感染重要病原菌，其生存能力、毒力和耐药水平相对于其它不动杆菌属菌种存在明显优势，已造成世界范围的广泛流行，临床治疗非常困难。本研究首先解决了不动杆菌属细菌的分类难题，从基因组水平为菌株分类提供了依据，并发现了一个不动杆菌属细菌的新种。紧接着通过收集的代表不同种或不同克隆型的不动杆菌属菌株，评估了它们在逆境中的生存能力，比较了对细胞的粘附、引起细胞凋亡、形成生物被膜等致病能力以及对大蜡螟幼虫、小鼠模型的毒力差异，发现鲍曼不动杆菌的致病力明显高于其它不动杆菌。同时，围绕不动杆菌重要的毒力相关Ⅵ型分泌系统，明确了vgrG在介导鲍曼不动杆菌致病力方面的作用。重点对鲍曼不动杆菌在临床上的进化进行了探索，发现其在病人体内有向同一克隆复合体演化的趋势，并且这种重要的克隆复合体在耐药性和水平转移途径上存在多样性，临床危害极大。另外，探索了以OXA型碳青霉烯酶基因为代表的耐药基因进化及水平转移机制，发现了耐药基因在鲍曼不动杆菌基因组中易出现多拷贝现象，并阐明了TEM-1酶和ADC-30酶对舒巴坦耐药的介导作用。本课题通过不同不动杆菌在致病力、耐药性上的比较，重点关注鲍曼不动杆菌的致病力和耐药性的机制和进化演变，明确了鲍曼不动杆菌的种优势性，揭示了其在临床环境中广泛传播的原因，为进一步寻求控制策略和指导临床治疗提供基础。