多重耐药鲍曼不动杆菌基因组流行病学特征及其暴发流行的预警新策略研究

The increasing incidence of A. baumannii has emerged worldwide as one of the most important opportunistic pathogens and is currently reported to be a worldwide nosocomial menace. It is also a great challenge to clinicians regarding how to monitor and prevent the hospital outbreaks. Previous study has confirmed that the high A. baumannii clonality creates difficulty in tracking outbreaks because the available methods may not provide sufficient resolution to distinguish intra-institutional spread from closely related strains. Our preliminary study has developed an A. baumannii cgMLST scheme and a progressive core genome phylogeny analysis strategy to distinguish isolates emerged in a single outbreak more precisely. Here, we propose to apply whole-genome sequencing to track the out breaks from 520 multi-drug resistance A. baumannii isolated in different hospitals recently. We also try to develop a new strategy to reconstruct the outbreak transmissions based on genomic epidemiological data. Finally, a new early warning database that is designed for the clinicians to monitoring the outbreaks and techniques to predict antibiotic resistance and virulence profile from omics data will also be developed. Our proposal may shed important light on further understanding the transmission scenarios of A. baumannii and could also help to guide future infection control decisions.

鲍曼不动杆菌临床分离率不断上升，给临床抗感染治疗与院感防控工作带来严峻挑战，如何对其进行有效监测与防控是临床面临的一大难题。现有研究表明，我国鲍曼不动杆菌呈克隆播散趋势，由于其院内单次暴发流行株的变异度极小，基于传统分型方法难以识别菌株间的细微差异，给鲍曼不动杆菌传播的追踪与溯源工作造成困难。我们在前期研究中，已初步设计出分辨率更高的鲍曼不动杆菌核心基因组MLST分型方案与递进式系统发育学数据分析策略，可准确区分单次暴发疫情中菌株的微小变异。本研究拟对我国多家医院连续分离的520株多重耐药鲍曼不动杆菌进行比较基因组学研究，以阐明其基因组流行病学特征。在此基础上，开发鲍曼不动杆菌院内感染暴发流行预警数据库，以追溯菌株来源与传播路线，同时探索基于组学手段解析鲍曼不动杆菌耐药与毒力特征的新技术。本研究可为阐明鲍曼不动杆菌的传播机制开辟新思路，也为今后制定合理的流行病学监测与防控措施提供科学依据。

鲍曼不动杆菌在全球的广泛传播与流行给临床抗感染治疗和院内感染控制带来严峻挑战，如何对其进行有效监测与精准溯源是院内感染防控的关键。本研究从临床关注的热点问题出发，对鲍曼不动杆菌基因组流行病学特征及其暴发流行溯源的关键技术进行深入研究。应用全基因组测序技术与生物信息学数据分析方法，构建鲍曼不动杆菌基因组分型与溯源在线数据分析平台BacWGSTdb，并建立鲍曼不动杆菌院内感染暴发流行精准溯源与预警关键技术。同时，应用高通量荧光定量PCR技术与多种统计学方法，结合鲍曼不动杆菌耐药基因的有无、基因拷贝数、表达量及其对多种不同类型抗菌药物的MIC，对全基因组测序在碳青霉烯耐药鲍曼不动杆菌的体外药物敏感性预测中的作用进行研究，并取得以下研究结果：① 阐明鲍曼不动杆菌的基因组流行病学特征，建立其院内暴发流行精准溯源关键技术；② 开发鲍曼不动杆菌基因组分型、溯源与院内暴发流行预警在线数据库BacWGSTdb，建立群体基因组学监测网络，实现及时发现并追溯院内暴发流行克隆的目标；③ 开发基于全基因组测序数据预测菌株耐药表型新方法，为临床微生物实验室提供快速、准确的鲍曼不动杆菌耐药性与致病性特征临床检验诊断报告。本研究从基因组流行病学角度阐释鲍曼不动杆菌的暴发流行规律与预警新策略，为探索鲍曼不动杆菌感染流行的传播机制提供新思路，也为如何有效监测、预警与防控多重耐药鲍曼不动杆菌这一重要临床问题提供可行的解决方案。