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.

抽象的 利用微生物组的宏基因组学来预测抗菌药物的定植/感染 耐药病原体（项目#2） 抗生素耐药性是对公共健康日益严重的全球威胁。耐万古霉素肠球菌（VRE）， 产生超广谱 β-内酰胺酶/耐碳青霉烯类肠杆菌 (ESBL-E/CRE) 和 艰难梭菌是关键的抗菌素耐药 (AMR) 病原体，其起始部位为肠道 殖民化。因此，肠道共生微生物群提供的定植抗性是 这些生物体病理生理学的关键方面。人类初级阶段的完成 微生物组项目提供了对微生物组如何影响感染的新认识，并已 产生了新的工具，以进一步推动人类​​健康这一关键领域的发展。另外，不偏不倚 细菌鉴定方法使人们越来越认识到 VRE、ESBL-E/CRE 和 C. 艰难梭菌经常在患者中共同定殖，这表明这些微生物除了 共生微生物区系。该项目的长期目标与 P01 提案的其他部分相协同， 目的是剖析共生微生物群、宿主和万能抗微生物药物之间相互作用的潜在机制， ESBL-E/CRE 和艰难梭菌会影响这些 AMR 病原体的肠道定植和随后的感染。 尽管众所周知，抗菌药物对微生物组的破坏是这些细菌定植的关键初始步骤 病原体，我们寻求解决关键知识差距，即为什么只有一小部分患者接受抗菌药物 被这些生物定植并最终感染。为此，我们建议进行纵向 对德克萨斯州两家不同医院的重症监护室和造血干细胞移植患者的研究 医疗中心。将根据初始和纵向定植状态对患者进行分类，并且 这些分类将与基于宏基因组学的连续粪便样本微生物组分析相关。 与计算生物学家合作，将挖掘特定物种或特定物种的宏基因组数据。 对定植和感染具有保护作用或与定植和感染呈正相关的物种组合， 包括共同殖民。此外，我们将测试临床队列中的样本是否可以保护小鼠 从 AMR 病原体挑战中验证临床观察到的关联。最后，我们还将使用动物 测试所研究的特定生物体先前存在的定植如何影响后续的模型 一种独特的 AMR 病原体定植。通过与微生物群专家、计算生物学家和 来自高度一体化的墨西哥湾沿岸抗菌素耐药性联盟的医生科学家，该提案 旨在加深对关键 AMR 病原体如何定植和感染人类的​​了解，以便提供 一个重要的平台，用于减轻抗菌素耐药性祸害的新型预防或治疗方法。