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

项目 1：病原体基因组学和从定植到感染的转变

• 批准号: 10226287
• 负责人: Cesar Augusto Arias
• 金额: $ 51.95万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226287
• 关键词: Affect; Algorithms; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Centers for Disease Control and Prevention (U.S.); Characteristics; Clinical; Clostridium difficile; Communicable Diseases; Critical Illness; Data; Development; Disease; Disease Progression; Disease susceptibility; Elements; Enterobacteriaceae; Event; Evolution; Extended-spectrum β-lactamase; Gastrointestinal tract structure; Genome; Genomics; Hematologic Neoplasms; Hospitals; Immune system; Immunocompromised Host; Individual; Infection; Intensive Care Units; Intestines; Mass Spectrum Analysis; Medical; Medical center; Metagenomics; Microbe; Monitor; Multi-Drug Resistance; Nature; Nosocomial Infections; Organism; Outcome; Pathogenesis; Patient Care; Patients; Plasmids; Play; Population; Population Dynamics; Predisposition; Process; Prospective cohort; Proteomics; Public Health; Reaction; Role; Severity of illness; Source; Stem cell transplant; Structure; Techniques; Technology; Texas; Time; Transplant Recipients; Transplantation; Vancomycin resistant enterococcus; Virulence; World Health; World Health Organization; antimicrobial; base; beta-Lactam Resistance; carbapenem-resistant Enterobacteriaceae; carbapenemase; clinical epidemiology; cohort; dysbiosis; gastrointestinal; genome sequencing; genomic epidemiology; genomic signature; genomic variation; gut colonization; high risk; host microbiome; insight; metabolomics; metaproteomics; microbial; microbiota; mortality; mouse model; multi-drug resistant pathogen; novel; pathobiont; pathogen; prevent; priority pathogen; programs; prospective; public health priorities; translational approach; translational study

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.

抽象的 病原体基因组学和从定植到感染的转变 （项目#1） 抗生素耐药性已成为重要的公共卫生优先事项，因为它会造成毁灭性的后果 可能对美国、世界健康和全球经济产生影响。在最顽固的病原体中，延长 谱 β-内酰胺酶和碳青霉烯酶产生肠杆菌科 (ESBL-E/CRE)、梭状芽胞杆菌 艰难梭菌和耐万古霉素肠球菌 (VRE) 属于最优先考虑的微生物。一个常见的 这些优先病原体的主题是肠道通常是主要的储存库和来源 院内感染。此外，关于临床传染病发病机制的大部分知识 这些生物体基于将症状性疾病视为本质上“单一微生物”的研究， 被认为是由单一病原体的毒力机制主导，没有显着的影响 其他微生物或病原体的贡献。此外，理解这一过程的一个重大挑战 病原体定植到危重病人感染的原因是这些个体被纳入研究 事件发生的时间（即它们被定植和/或感染的时间）。这种情况阻碍了关键机制 深入了解为什么只有一小部分易感患者会出现病原体定植和随后的感染 以及此过程发生时导致死亡率增加的因素。我们的初步数据表明，功能 这些生物体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 在脆弱的患者中。利用休斯顿德克萨斯医疗中心的设施，我们计划前瞻性地 跟踪两个强大的免疫功能低下和危重患者队列，即患有以下疾病的患者 接受干细胞移植（SCT）移植的血液恶性肿瘤和危重患者 住进重症监护病房 (ICU)。这些患者的护理的一个共同特点是大量的 使用抗菌药物导致胃肠道生态失调。我们的假设，作为本 P01 的一部分 应用程序（DYNAMITE 程序）是指患者对肠道源性医院定植/感染的易感性 高威胁 AMR 病原体的抵抗力很大程度上取决于病原体的适应性（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-病原体相互作用 进展和临床结果。该项目的具体目标是，i）剖析人口结构 VRE、ESBL-E/CRE 和艰难梭菌在定植与感染分离株中的关系，ii) 识别 VRE 中的基因组特征， ESBL-E/CRE 和艰难梭菌与主要临床结果相关，并剖析了其临床影响 高危患者中的定植，以及 iii) 确定抗生素使用对定植动态的影响 这些肠道源性病原体的定植/感染和抗生素耐药性的发展。我们的 DYNAMITE 计划的综合转化方法，结合了基因组学、宏基因组学、 蛋白质组学/代谢组学和临床特征将为影响影响的主要因素提供新的见解 重症和免疫功能低下患者的结果。