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

基本信息

批准号：
10614693
负责人：
Cesar Augusto Arias
金额：
$ 37.58万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614693
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

项目摘要

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。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万古霉素耐药肠球菌 (VRE) 是最优先考虑的常见微生物。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此外，关于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，没有显着的影响此外，了解其他微生物或病原体的贡献也是一个重大挑战。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（即当它们被定殖和/或感染时）。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当这个过程发生时增加死亡率的因素。我们的初步数据表明，这是功能性的。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我们计划利用休斯顿德克萨斯医疗中心的设施，前瞻性地针对弱势患者进行治疗。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入住医疗重症监护病房 (ICU) 的一个共同特点是患者数量庞大。作为本 P01 的一部分，我们的假设是使用抗菌药物导致胃肠道生态失调。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。 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。