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

摘要 利用微生物组的宏基因组学预测抗菌剂的定植/感染- 耐药病原体（项目#2） 抗生素耐药性是对公共卫生日益严重的全球威胁。万古霉素耐药肠球菌（VRE）， 产超广谱β-内酰胺酶/碳青霉烯类耐药肠杆菌科（ESBL-E/CRE）和 艰难梭菌是主要的耐药性（AMR）病原体，它们共享肠道作为初始位点 殖民化。因此，由肠道的肠道微生物群提供的定植抗性是一种有效的方法。 这些生物体的病理生理学的关键方面。完成人类的初始阶段 微生物组项目为微生物组如何影响感染提供了新的理解， 为人类健康这一关键领域的进一步发展创造了新的工具。此外，无偏 细菌鉴定的方法导致越来越多的人认识到VRE、ESBL-E/CRE和C. 艰难梭菌通常共同定殖于患者，这表明这些微生物除了相互作用外， 微生物群落本项目的长期目标与本P01提案的其他部分协同， 是要剖析潜在的机制，如何相互作用之间的肠道微生物区系，主机，和VRE， ESBL-E/CRE和C.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，抗微生物剂对微生物组的破坏是这些细菌定殖的关键初始步骤， 病原体，我们寻求解决关键的知识差距，为什么只有一个子集的患者接受抗菌药物 成为殖民地并最终被这些生物体感染。为此，我们建议执行纵向 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 医学中心患者将根据初始和纵向定植状态进行分类， 这些分类将与连续粪便样品的基于宏基因组学的微生物组分析相关联。 与计算生物学家合作，宏基因组学数据将被挖掘用于特定物种或 对定植和感染具有保护作用或与定植和感染正相关的物种的组合， 包括共同殖民。此外，我们将测试来自临床队列的样本是否可以保护小鼠 从AMR病原体挑战，以验证临床观察到的关联。最后，我们还将使用动物 模型来测试预先存在的殖民与研究中的特定生物如何影响随后的 由不同的AMR病原体定殖。通过与微生物群专家、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科学家， 旨在加深对关键AMR病原体如何定殖和感染人类的理解， 一个重要的平台，用于新的预防或治疗方法，以减轻AMR祸害。

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.