Project 3: Functional Microbiome and Host Signatures in Transition from Commensal to pathogen

摘要 项目3：从共生体到病原体转变中的功能性微生物组和宿主特征 抗生素的过度使用和细菌的适应性导致了病原菌的抗菌药物耐药性（AMR） 严重的公共卫生问题识别易受感染的个体至关重要， 实施有效的治疗计划和促进良好的抗菌管理。该项目重点 开发创新系统技术，以开发基于微生物组的风险算法， 一般住院人群中的易感患者。正在测试的项目前提是， 定植于肠道的病原体专门针对具有不成熟的婴儿样肠道微生物群的个体 允许病原体定植的特征。我们研究的主要AMR病原体包括 艰难梭菌，万古霉素耐药肠球菌（VRE），碳青霉烯耐药肺炎克雷伯菌， 和产超广谱β-内酰胺酶肠杆菌（ESBL-E/CRE），因为这些微生物 在引起感染之前通常会在肠道内定植。具体来说，我们表明，这些优先病原体往往 共同定植那些缺少关键微生物群物种的脆弱患者，这些微生物群物种似乎广泛存在于 通过产生不同的细菌素来抵抗这些细菌。在此PO 1应用程序的项目3中，我们将 对这些独特的宿主-微生物群-病原体相互作用进行协同功能分析， 以下两个具体目标： 目标3.1。定义代谢活性微生物群群落结构， 易感患者的病原体定植和疾病进展。 目标3.2。表征关键微生物群特征及其保护性抗菌剂 机制等 这项研究是有影响力的，因为我们打算建立预测微生物群风险算法，以提高精度。 免疫抑制和重症患者的感染管理。长期目标是建议 医生和医疗保健利益相关者的临床监测和治疗干预， 每个人的感染所造成的，以及定义宿主-微生物群-病原体相互作用是允许的 其他新出现的感染。

ABSTRACT Project 3: Functional Microbiome and Host Signatures in Transition from Commensal to pathogen Overuse of antibiotics and adaptability of bacteria has resulted in antimicrobial resistance (AMR) in pathogens of significant public health concern. Identifying individuals who are susceptible to infection is critical in implementing an effective treatment plan and in promoting good antimicrobial stewardship. This project focuses on developing innovative systems technology to develop microbiome-based risk algorithms that identify susceptible patients in the general hospitalized population. The project premise being tested is that nosocomial pathogens that colonize the intestines specifically target individuals with immature infant-like gut microbiota features that are permissive to pathogen colonization. The notable AMR-pathogens of our study include Clostridioides difficile, vancomycin-resistant enterococcus (VRE), carbapenem-resistant Klebsiella pneumoniae, and extended spectrum β-lactamase producing Enterobacteriacae (ESBL-E/CRE) because these organisms often colonize the intestines before causing infection. Specifically, we show that these priority pathogens often co-colonize vulnerable patients who are missing keystone microbiota species that appear to be broadly protective against these bacteria by producing diverse bacteriocins. In Project 3 of this PO1 application, we will perform synergistic functional profiling of these unique host-microbiota-pathogen interactions to address the following two specific aims: • Aim 3.1. Define the metabolically active microbiota community structure identified with pathogen colonization and disease progression in the susceptible patient. • Aim 3.2. Characterize keystone microbiota features and their protective antimicrobial mechanisms. The study is impactful because we intend to establish predictive microbiome-risk algorithms for precision infection management of immunosuppressed and critically ill patients. The long-term goal is to advise the physician and healthcare stakeholders of clinical surveillance and therapeutic interventions that match the risk posed by each individual’s infection, as well as define host-microbiota-pathogen interactions that are permissive to other emerging infections.