Genomics of bacterial pathogens: host response, persistence and transmission

近80年前抗生素的发现是对抗传染性疾病斗争的一个重要里程碑。 然而，细菌感染仍然是世界范围内死亡的一个重要原因。事实上，管理层 许多细菌感染的治疗正变得越来越困难，因为新的和 快速进化的病原体具有更高的毒力、对抗生素的抗药性、更强的逃避宿主的能力 反应，并提高了传播性。为了扭转这一趋势，系统地理解复杂的 病原体和寄主之间的相互作用在各个层面上都是需要的，包括 细胞、个体、微生物群落和种群。 我们将开发和实施一个综合实验框架，提供系统和 对细菌感染的补充见解，包括单细胞、动物模型和人类 研究细胞基因组学、转录网络和宿主微生态。其中三个 大多数致命和昂贵的细菌病原体将被用作开发这一框架和探测的例子 寄主-病原菌相互作用。具体地说，我们将剖析分支杆菌之间的相互作用 结核病及其宿主在单细胞水平上获得深入和高度分辨的特征 导致感染易感性的宿主细胞状态。我们将遵循以下动态 尿路致病性大肠埃希氏菌(UPEC)在动物和人类中的感染 UPEC、宿主和宿主微生物群在反复尿路感染中的持续性。我们会追踪 耐碳青霉烯类肠杆菌科细菌(CRE)在体内的迁移和进化 患者群体提供了有关CRE及其携带的耐药因素的关键细节 在患者和患者群体之间传播。 这项工作有两个目标。一是开发一个可适应的多组学方法框架，以 适用于广泛的病原体，用于解剖细菌感染的单个细胞，感染 个人和临床人口水平。第二个是利用这个框架的成果来 辨识点

The discovery of antibiotics nearly 80 years ago was a major milestone in the battle against infectious disease, yet bacterial infections continue to be a significant cause of death worldwide. In fact, management of many bacterial infections is becoming progressively more difficult due to the emergence of new and rapidly evolving pathogens with increased virulence, resistance to antibiotics, a greater ability to evade host responses, and heightened transmissibility. To reverse this trend, a systematic understanding of the complex dynamics between the pathogen and host is needed at every level of interaction, including those between cells, individuals, microbial communities, and populations. We will develop and implement an integrated experimental framework that provides systematic and complementary insights into bacterial infections encompassing single cells, animal models, and human patients, to investigate cellular genomics, transcriptional networks, and host microecologies. Three of the most deadly and costly bacterial pathogens will be used as examples to develop this framework and probe the host-pathogen interaction. Specifically, we will dissect the interaction between Mycobacterium tuberculosis and its host at the single cell level to gain a deep and highly resolved characterization of the host cellular states that contribute to susceptibility to infection. We will follow the dynamics of uropathogenic Escherichia coli (UPEC) infection in animals and humans to gain insights into the role of UPEC, the host and the host microbiome in the persistence of recurrent urinary tract infections. We will track the movement and evolution of carbapenem resistant Enterobacteriaceae (CRE) as they emerge in patient populations contributing critical details about how CRE and the resistance elements that they carry are transmitted among patients and patient populations. There are two goals of this work. One is to develop an adaptable framework of multi-omic approaches to be applied to a wide-range of pathogens for the dissection of bacterial infection at the single cell, infected individual and clinical population levels. The second is to capitalize on the output from this framework to identify points