Project 2 Defining multiscale dynamics of strains, genes and resistance in bacterial pathogens

项目摘要 尽管抗生素已经问世，但每年全世界仍有数百万人死于细菌性疾病 九十年前。新的和迅速演变的病原体的出现和传播， 毒力、抗生素耐药性和传染性使我们的努力越来越紧张， 控制感染和拯救生命。为了遏制这一趋势，我们需要一个全面和 系统地了解宿主，包括宿主微生物群， 和病原体在每一个层次的相互作用-细胞，个人，和人口水平。我们 拟议的研究利用了测序技术的最新进展， 高通量分子和多组学方法，获得独特的患者队列，以及 新的计算方法来表征基因组，转录组，和个人 细菌病原体与其宿主和其他微生物群的菌株水平相互作用。在 我们与著名的传染病研究人员、临床医生和流行病学家合作， 将针对我们对关键传染病威胁的理解中的关键差距-尿路感染 大肠埃希菌（UPEC）、碳青霉烯耐药肠杆菌科（CRE）和多药耐药肠杆菌科（CRE） 耐药肠球菌具体而言，我们将（i） 确定UPEC的肠道-尿路动力学 复发性尿路感染; ii）跟踪抗生素耐药性的多尺度动态 基因增殖-从个体微生物群到局部和全球循环;以及iii）表征 MDR肠球菌的动态功能库。虽然我们的目标集中在ESKAPE 病原体，我们的目标是开拓和传播一个全面的 技术框架 和资源，使临床和研究社区能够了解，诊断， 预防和治疗传染病。

Project Summary Bacterial diseases kill millions of people worldwide each year, despite the advent of antibiotics 90 years ago. Emergence and spread of new and rapidly evolving pathogens with increased virulence, resistance to antibiotics, and transmissibility is increasingly straining efforts to manage infections and save lives. To combat this trend, we need a comprehensive and systematic understanding of the complex dynamics between the host, including host microbiota, and pathogen at every level of interaction—cellular, individual, and population levels. Our proposed studies leverage recent advances in sequencing technologies, innovative high-throughput molecular and multi-omic approaches, access to unique patient cohorts, and novel computational methods to characterize the genomes, transcriptomes, and individual strain-level interactions of bacterial pathogens with their hosts and other microbiota. In collaboration with renowned infectious disease researchers, clinicians, and epidemiologists, we will target critical gaps in our understanding of key infectious disease threats—uropathogenic E​scherichia coli (UPEC), carbapenem resistant ​Enter​obacteriaceae (CRE), and multidrug resistant enterococci. Specifically, we will i)​ ​determine the gut-to-urinary tract dynamics of UPEC in recurrent urinary tract infections; ii) track the multiscale dynamics of antibiotic resistance gene proliferation - from individual microbiota to local and global circulation; and iii) characterize the dynamic functional reservoir of MDR enterococci. While our aims focus on ESKAPE pathogens, our goal is to pioneer and disseminate a ​comprehensive​ ​technological framework and resources to empower clinical and research communities working to understand, diagnose, prevent, and treat infectious diseases.