Project 2: Leveraging Metagenomics of the Microbiome to predict colonization/infection by antimicrobial-resistant pathogens

项目 2：利用微生物组的宏基因组学来预测耐药病原体的定植/感染

• 批准号: 10614694
• 负责人: SAMUEL A SHELBURNE
• 金额: $ 54.31万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614694
• 关键词: Address; Animal Model; Antimicrobial Resistance; Area; Characteristics; Classification; Clinical; Clinical Data; Clinical Research; Clostridium difficile; Cohort Studies; Communicable Diseases; Critical Illness; Data; Data Analyses; Development; Elements; Extended-spectrum β-lactamase; Feces; Functional disorder; Genomics; Goals; Health; Hematopoietic Stem Cell Transplantation; Hospitals; Human; Human Microbiome; Immunocompromised Host; Infection; Intensive Care Units; Intestines; Knowledge; Length of Stay; Longitudinal Studies; Mediating; Medical center; Metagenomics; Mus; Nature; Organism; Pathogenesis; Patients; Physicians; Predisposition; Preventive; Protocols documentation; Public Health; Publishing; Research; Resistance; Ribosomal RNA; Risk; Sampling; Scientist; Scourge; Signal Transduction; Site; System; Systems Biology; Testing; Texas; Therapeutic; Transplant Recipients; Vancomycin resistant enterococcus; Work; antimicrobial; antimicrobial resistant infection; antimicrobial resistant pathogen; base; carbapenem-resistant Enterobacteriaceae; cohort; colonization resistance; commensal microbes; deep sequencing; drug resistant pathogen; gulf coast; gut colonization; gut microbiome; gut microbiota; high risk; indexing; insight; microbiome; microbiome analysis; microbiome composition; microbiota; microbiota profiles; multi-drug resistant pathogen; new technology; novel; pathogen; patient population; patient subsets; programs; risk stratification; stool sample; synergism; tool

ABSTRACT Leveraging Metagenomics of the Microbiome to Predict Colonization/Infection by Antimicrobial- Resistant Pathogens (Project #2) Antimicrobial resistance is a growing, global threat to public health. Vancomycin-resistant enterococci (VRE), extended spectrum β-lactamase producing/carbapenem-resistant Enterobacteriaceae (ESBL-E/CRE) and Clostridiodes difficile are key antimicrobial resistant (AMR) pathogens that share the intestine as the initial site of colonization. Therefore, colonization resistance provided by the commensal microbiota of the intestines is a critical aspect of the pathophysiology of these organisms. The completion of the initial stages of the Human Microbiome Project has provided new understanding of how the microbiome impacts infections and has generated novel tools for further advances in this critical area of human health. Additionally, unbiased approaches to bacterial identification have resulted in increasing appreciation that VRE, ESBL-E/CRE, and C. difficile often co-colonize patients suggesting that these organisms are interacting with each other in addition to the commensal microflora. The long term goals of this project, in synergy with other portions of this P01 proposal, are to dissect the mechanisms underlying how interactions among the commensal microflora, the host, and VRE, ESBL-E/CRE, and C. difficile impact intestinal colonization and subsequent infection by these AMR pathogens. Although it is well known that microbiome disruption by antimicrobials is a key initial step in colonization by these pathogens, we seek to address the key knowledge gap of why only a subset of patients receiving antimicrobials become colonized and eventually infected by these organisms. To this end, we propose performing longitudinal studies of intensive care unit and hematopoietic stem cell transplant patients at two distinct hospitals in the Texas Medical Center. Patients will be classified depending on both initial and longitudinal colonization status, and these classifications will be correlated with metagenomics based microbiome analyses of serial stool samples. In concert with computational biologists, the metagenomics data will be mined for particularly species or combinations of species that are either protective against or positively associated with colonization and infection, including co-colonization. Additionally, we will test whether samples from the clinical cohort can protect mice from AMR pathogen challenge to validate associations observed clinically. Finally, we will also use animal models to test how pre-existing colonization with a particular organism under study impacts subsequent colonization by a distinct AMR pathogen. By synergizing with microbiota experts, computational biologists, and physician-scientists from the highly integrated Gulf Coast Consortium on Antimicrobial Resistance, this proposal seeks to sharpen understanding of how critical AMR pathogens colonize and infect humans in order to provide a critical platform for novel preventive or therapeutic approaches to mitigate the AMR scourge.

摘要