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

摘要 利用微生物组的元基因组学预测抗菌素的定植/感染 耐药病原体(项目2) 抗菌素耐药性是一个日益严重的全球公共卫生威胁。耐万古霉素肠球菌(VRE)， 产超广谱β-内酰胺酶/耐碳青霉烯肠杆菌科(ESBL-E/Cre)和 艰难梭菌是主要的抗菌素耐药(AMR)病原体，它们共享肠道作为起始部位 殖民主义的影响。因此，肠道共生微生物群提供的定植抗性是一种 这些生物体的病理生理学的关键方面。人类社会初始阶段的完成 微生物组项目为微生物组如何影响感染提供了新的理解，并已 为在这一人类健康的关键领域取得进一步进展创造了新的工具。此外，不带偏见 细菌鉴定的方法使人们越来越认识到VRE、ESBL-E/Cre和C. 艰难梭菌经常与患者共同定居，这表明这些微生物除了 共生微生物区系。本项目的长期目标，与本P01提案的其他部分协同， 是剖析共生微生物区系、寄主和VRE之间相互作用的潜在机制， ESBL-E/Cre和艰难梭菌影响肠道定植和随后由这些AMR病原体感染。 尽管众所周知，抗菌剂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，我们试图解决为什么只有一小部分患者接受抗菌药的关键知识差距 成为殖民地，并最终被这些生物感染。为此，我们建议纵向执行 德克萨斯州两家不同医院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居状态进行分类，以及 这些分类将与基于微基因组学的连续粪便样本的微生物组分析相关联。 与计算生物学家合作，将针对特定物种或物种挖掘元基因组数据 对殖民和感染具有保护作用或与之正相关的物种组合， 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病原体挑战来验证临床观察到的相关性。最后，我们还将使用动物 测试先前存在的对正在研究的特定生物体的定植如何影响后续 由一种不同的AMR病原体定植。通过与微生物区系专家、计算生物学家和 来自高度整合的墨西哥湾沿岸抗菌素耐药性联盟的医生和科学家，这项建议 旨在加深对关键的AMR病原体如何定植和感染人类的理解，以提供 为减轻AMR祸害的新的预防或治疗方法提供了一个关键平台。

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.