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

摘要 病原菌基因组学与从定植到感染的转变 (项目#1) 抗生素耐药性已成为关键的公共卫生优先事项，因为它造成的破坏性后果 可能会对美国、世界卫生和全球经济产生影响。在最顽固的病原体中，延长了 产β-内酰胺酶和碳青霉烯酶肠杆菌科(ESBL-E/Cre)，梭状杆菌 艰难梭菌和万古霉素耐药肠球菌(VRE)是最优先考虑的细菌之一。一种常见的 在这些优先病原体中，主题是肠道通常是主要的储藏者和来源 医院感染。此外，大多数已知的临床感染性疾病发病机制 这些生物体是基于一些研究，这些研究认为症状性疾病本质上是“单一微生物”的， 被认为仅由单一病原体的毒力机制主导的，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 病原体在危重病人感染中的定植是这些人被捕获到研究中 事件发生的时间(即它们成为殖民地和/或感染的时间)。这种情况阻止了关键机械 对为什么只有一小部分易感染患者会出现病原体定植和后续感染的见解 以及当这一过程发生时增加死亡率的因素。我们的初步数据显示，功能性 这些微生物之间的相互作用是临床疾病易感性和严重程度的重要决定因素。 在脆弱的病人身上。利用休斯顿德克萨斯医疗中心的设施，我们计划前瞻性地 跟踪免疫功能高度受损和危重患者的两个强有力的队列，即 接受干细胞移植(SCT)的血液系统恶性肿瘤和危重患者 住进内科重症监护病房(ICU)。护理这些患者的一个共同特点是 使用抗菌剂导致胃肠道生物失调。我们的假设，作为P01的一部分 应用(炸药计划)是患者对肠源性医院定植/感染的易感性 由高威胁的AMR病原体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)和决定疾病的宿主-微生物组-病原体的相互作用 进展和临床结果。该项目的具体目标是：i)剖析 VRE、ESBL-E/Cre和艰难梭菌在定植和感染分离株中的比较，II)鉴定VRE的基因组特征， 与主要临床结局相关的ESBL-E/Cre和艰难梭菌 在高危患者中的定植，以及iii)确定抗生素使用对动态的影响 这些肠道来源的病原体的定植/感染和抗生素耐药性的发展。我们的 爆炸性计划的全面翻译方法，融合了基因组学、元基因组学、 蛋白质组学/代谢组学和临床特征将为影响 危重患者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.