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预测抗菌 - 抵抗病原体（项目＃2） 抗菌抗性是对公共卫生的日益增长的全球威胁。抗性霉素肠球菌（VRE）， 扩展的光谱β-内酰胺酶产生/碳青霉烯耐药性肠杆菌科（ESBL-E/CRE）和 梭状芽胞杆菌艰难梭菌是关键的抗菌素耐药（AMR）病原体，该病原体共享肠道作为初始部位 殖民化。因此，由肠道的共生微生物群提供的定殖抗性是 这些生物的病理生理学的关键方面。人类初始阶段的完成 微生物组项目已经对微生物组如何影响感染提供了新的了解，并具有 生成了新的工具，以进一步发展在人类健康的关键领域。另外，公正 细菌鉴定的方法导致人们对VRE，ESBL-E/CRE和C. 艰难梭菌通常是共同殖民的患者，表明这些生物除了 共生菌群。该项目的长期目标与该P01提案的其他部分协同作用， 要剖析共生微生物，宿主和VRE之间相互作用的基础机制 ESBL-E/CRE和艰难梭菌会影响这些AMR病原体的肠道定植以及随后的感染。 尽管众所周知，抗微生物造成的微生物组破坏是这些殖民地的关键第一步 病原体，我们试图解决为什么只有接受抗菌药物的患者的一部分的关键知识差距 被殖民并最终被这些生物感染。为此，我们建议执行纵向 在德克萨斯州的两家不同医院的重症监护病房和造血干细胞移植患者的研究 医疗中心。患者将根据初始和纵向定殖身份进行分类，以及 这些类别将与基于元基因组学的串行粪便样品的微生物组分析相关。 在与计算生物学家协同的一致中，将针对物种或 受保护或与定殖和感染相关的物种的组合， 包括共殖化。此外，我们将测试来自临床队列的样品是否可以保护小鼠 从AMR病原体挑战到验证临床观察到的关联。最后，我们还将使用动物 测试在研究下与特定生物的预先存在定殖的模型会影响随后的影响 通过独特的AMR病原体定植。通过与菌群专家，计算生物学家和 来自高度综合墨西哥湾沿岸抗菌素抵抗的物理科学家，该提案 试图加深了解关键的AMR病原体如何定植和感染人类，以提供 一种新型预防或治疗方法来减轻AMR祸害的关键平台。