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 病原体的基因组学和从定植到感染的过渡 （项目＃1） 抗生素耐药性已成为关键的公共卫生优先事项，因为它的后果是 可能在美国，世界卫生和全球经济上拥有。在最顽固的病原体中，延伸 频谱β-内酰胺酶和碳青霉酶产生的肠杆菌科（ESBL-E/CRE），梭状芽胞杆菌 艰难梭菌和万古霉素的肠球菌（VRE）是最高的优先生物之一。常见 这些优先病原体的主题是肠道通常是主要储层和来源 医院感染。此外，关于临床传染病发病机理的大多数 这些生物基于研究，将症状性疾病视为“单微生物”本质上， 仅凭单一病原体的病毒机制而被认为没有明显的病毒机制 来自其他微生物或病原体的贡献。此外，要了解过程的主要挑战 病原体在重症患者中的感染是感染的，是将这些人捕获到研究中 事件发作时间（即殖民和/或感染的时间）。这种情况阻止了关键机理 了解为什么只有一部分脆弱患者会发展病原体定植和随后的感染 以及在此过程发生时增加死亡率的因素。我们的初步数据表明功能性 这些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剂 在脆弱的患者中。使用休斯顿德克萨斯医疗中心的设施，我们计划前景 遵循两个强大的高度免疫功能低下和重症患者的鲁棒人群，即患者 受干细胞移植（SCT）移植的血液系统恶性肿瘤和患病患者 接受医疗重症监护病房（ICU）。这些患者护理的一个共同特征是大量 在胃肠道上使用抗菌剂。我们的假设，作为该P01的一部分 应用（炸药计划）是患者对肠道衍生的医院定殖/感染的敏感性 通过高威胁的AMR病原体，密切取决于病原体的适应性（包括获得 抗生素耐药性决定了决定疾病的宿主 - 微生物组病原体相互作用 进展和临床结果。该项目的具体目的是，i）剖析 VRE，ESBL-E/CRE和艰难梭菌在定植与感染分离株中，ii）识别VRE中的基因组特征， ESBL-E/CRE和艰难梭菌与主要的临床结果相关，并剖析了 高危患者的定殖，以及iii）确定使用抗生素对动力学的影响 在这些肠道衍生的病原体中，定植/感染和抗生素耐药性的发展。我们的 炸药计划的全面翻译方法，编码基因组学，宏基因组学， 蛋白质组学/代谢组学和临床特征将为影响主要因素提供新的见解 重病和免疫功能低下的患者的结果。