Project 1: Genomics of Pathobionts and Transition From Colonization to Infection

摘要 致病菌的基因组学与从定殖到感染的转变 （项目#1） 抗生素耐药性已成为一个关键的公共卫生优先事项，由于它的破坏性后果， 对美国、世界健康和全球经济的影响。在最难对付的病原体中， 产β-内酰胺酶和碳青霉烯酶肠杆菌科（ESBL-E/CRE）、梭菌 艰难梭菌和万古霉素耐药肠球菌（VRE）是最优先的生物体。一个共同 这些优先病原体的主题是，肠道通常是主要的水库和来源， 院内感染此外，大多数关于临床感染性疾病发病机制的已知信息都是 这些微生物是基于将症状性疾病视为自然界中的"单一微生物"的研究， 被认为是由单一病原体的毒力机制所主导，而没有显著的 来自其他微生物或病原体的贡献。此外，理解这一过程的一个主要挑战是， 病原体定殖对重症患者感染的影响是，这些个体被纳入研究， 事件发生的时间（即，当它们被定殖和/或感染时）。这种情况防止了关键的机械性 深入了解为什么只有一部分脆弱的患者会发生病原体定植和随后的感染 以及当这个过程发生时增加死亡率的因素。我们的初步数据显示， 这些微生物之间的相互作用是临床疾病易感性和严重性的重要决定因素 脆弱的病人。利用休斯顿德克萨斯医疗中心的设施，我们计划前瞻性地 遵循两个强大的队列高度免疫功能低下和危重患者，即患者 接受干细胞移植（SCT）移植的血液恶性肿瘤和那些危重患者 入住重症监护室（ICU）。这些患者护理的一个共同特点是大量的 使用抗菌剂导致胃肠道生态失调。我们的假设，作为P01的一部分， 应用程序（EQUIPITE程序）是患者对肠道来源的医院定植/感染的易感性 高威胁AMR病原体的感染严重依赖于病原体的适应性（包括获得 抗生素耐药性决定因素）和宿主-微生物组-病原体相互作用， 进展和临床结果。这一项目的具体目标是：（一）剖析 VRE、ESBL-E/CRE和C. ii）鉴定VRE中的基因组特征， ESBL-E/CRE和C.与主要临床结局相关并分析 高危患者中的定植，以及iii）确定抗生素使用对 这些肠道来源的病原体的定植/感染和抗生素抗性的发展。我们 综合翻译的方法，将基因组学，宏基因组学， 蛋白质组学/代谢组学和临床特征将提供新的见解的主要因素， 重症和免疫功能低下患者的结局。

ABSTRACT Genomics of Pathobionts and Transition From Colonization to Infection (Project #1) Antibiotic resistance has become a critical public health priority due to the devastating consequences that it may have on the US, world health and global economy. Among the most recalcitrant pathogens, extended spectrum β-lactamase and carbapenemase-producing Enterobacteriaceae (ESBL-E/CRE), Clostridiodes difficile and vancomycin-resistant enterococci (VRE) are among the highest priority organisms. A common theme among these priority pathogens is that the intestine is usually the major reservoir and source of nosocomial infections. Additionally, most of what is known about clinical infectious disease pathogenesis of these organisms is based on studies that view symptomatic disease as being “mono-microbial” in nature, considered to be dominated by the virulence mechanisms of a single pathogen alone without significant contributions from other microbes or pathogens. Moreover, a major challenge to understand the process of pathogen colonization to infection in critically ill patients is that these individuals are captured into studies at the time of event onset (i.e. when they become colonized and/or infected). This situation prevents key mechanistic insights into why only a subset of vulnerable patients develop pathogen colonization and subsequent infection and the factors that increase mortality when this process occurs. Our preliminary data show that functional interactions between these organisms are important determinants of clinical disease susceptibility and severity in vulnerable patients. Using the facilities of the Houston’s Texas Medical Center, we plan to prospectively follow two robust cohorts of highly immunocompromised and critically ill patients, namely, patients with hematological malignancies subjected to stem cell transplant (SCT) transplant and those critically ill individuals admitted to medical intensive care units (ICUs). A common feature in the care of these patients is the massive use of antimicrobials causing dysbiosis on the gastrointestinal tract. Our hypothesis, as part of this P01 application (DYNAMITE program) is that patient susceptibility to gut-derived nosocomial colonization/infection by high-threat AMR pathogens is critically dependent on pathogen adaptability (including acquisition of antibiotic resistance determinants) and host-microbiome-pathogen interactions that determine disease progression and clinical outcomes. The specific aims of this project are, i) dissect the population structure of VRE, ESBL-E/CRE and C. difficile in colonizing vs infecting isolates, ii) Identify genomic features in VRE, ESBL-E/CRE and C. difficile that correlate with major clinical outcomes and dissect the clinical impact of colonization in high-risk patients, and iii) determine the impact of antibiotic use on the dynamics of colonization/infection and development of antibiotic resistance in these gut-derived pathogens. Our comprehensive translational approach of the DYNAMITE program, incorporating genomics, metagenomics, proteomics/metabolomics and clinical features would provide novel insights into major factors that influence outcomes of critically ill and immunocompromised patients.