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

摘要 项目3：从共生菌向病原体过渡的功能微生物组和宿主特征 过度使用抗生素和细菌的适应性导致病原菌产生抗菌素耐药性(AMR) 严重的公共卫生问题。识别易受感染的个人在 实施有效的治疗计划，促进良好的抗菌素管理。这个项目的重点是 关于开发创新的系统技术以开发基于微生物组的风险算法来识别 普通住院人群中的易感患者。正在测试的项目前提是医院 定植于肠道的病原体专门针对具有未成熟婴儿样肠道微生物区系的个体 允许病原体定植的特征。我们研究中值得注意的AMR病原体包括 艰难梭状杆菌，耐万古霉素肠球菌，碳青霉烯类耐药肺炎克雷伯菌， 和产超广谱β-内酰胺酶的肠杆菌(ESBL-E/Cre)，因为这些细菌 通常在引起感染之前定植在肠道上。具体地说，我们发现这些优先病原体通常 共同殖民那些缺少Keystone微生物区系物种的脆弱患者 通过产生不同的细菌素来防御这些细菌。在此PO1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，以解决 以下是两个具体目标： ·目标3.1。确定具有代谢活性的微生物群落结构 易感患者的病原体定植和疾病进展。 ·目标3.2。Keystone微生物区系特征及其保护性抗菌剂的研究 机械装置。 这项研究很有影响力，因为我们打算建立预测微生物组风险的算法，以确保精确度 免疫抑制和危重病人的感染管理。我们的长期目标是向 与风险匹配的临床监测和治疗干预的医生和医疗保健利益相关者 以及定义允许的宿主-微生物群-病原体相互作用 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.