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

项目摘要 尽管抗生素问世，但全世界每年仍有数百万人死于细菌性疾病。 90年前。新的和快速进化的病原体的出现和传播 毒力、对抗生素的抗药性和传播性正在日益紧张地努力 控制感染并拯救生命。为了应对这一趋势，我们需要一个全面和 系统地了解寄主之间的复杂动态，包括寄主微生物群， 以及病原体在各个层面的相互作用--细胞、个人和群体层面。我们的 拟议的研究利用了测序技术的最新进展，具有创新性 高通量分子和多组学方法，获得独特的患者队列，以及 描述基因组、转录本和个体的新的计算方法 细菌病原体与它们的宿主和其他微生物区系的菌株水平的相互作用。在……里面 与著名传染病研究人员、临床医生和流行病学家合作，我们 将针对我们对主要传染病威胁--泌尿系致病的认识上的严重差距 E-​大肠埃希菌、耐碳青霉烯类​进入​杆菌科(Cre)、多药耐药 耐药肠球菌。具体地说，我们将i)​​确定UPEC的肠道到尿路动力学 在复发性尿路感染中；ii)追踪抗生素耐药性的多尺度动态 基因增殖--从单个微生物区系到局部和全球循环；以及三)特征 耐多药肠球菌的动态功能储备库。虽然我们的目标集中在ESKAPE 病原体，我们的目标是开创和传播​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.