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

项目 3：从共生到病原体转变的功能微生物组和宿主特征

• 批准号: 10024961
• 负责人: Tor C. Savidge
• 金额: $ 49.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10024961
• 关键词: Achievement; Address; Adult; Algorithms; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Clinical; Clinical Management; Clostridium difficile; Communicable Diseases; Communities; Critical Illness; Data; Development; Disease; Disease Outcome; Disease Progression; Disease susceptibility; Extended-spectrum β-lactamase; Goals; Healthcare; Immune response; Immunocompromised Host; Indigenous; Individual; Infant; Infection; Intensive Care Units; Link; Medical; Metabolic; Metabolic Pathway; Metagenomics; Modern Medicine; Nosocomial Infections; Organism; Outcome; Patients; Physicians; Population; Predisposition; Public Health; Publishing; Resistance; Risk; Risk Factors; Shotguns; Signal Transduction; Stem cell transplant; Structure; System; Technology; Testing; Therapeutic Intervention; Transplant Recipients; Vancomycin resistant enterococcus; Virulence; antimicrobial; bacteriocin; base; carbapenem resistance; cohort; combat; design; effective therapy; functional genomics; gut colonization; gut microbiota; hazard; high risk; host microbiota; immunosuppressed; infection management; infection risk; infectious disease model; innovation; insight; metabolic profile; metaproteomics; microbiome; microbiota; multi-drug resistant pathogen; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; prevent; priority pathogen; prospective; resistant Klebsiella pneumoniae; trait; treatment planning

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.

抽象的 项目 3：从共生到病原体转变的功能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病原体产生抗菌素耐药性（AMR） 具有重大的公共卫生问题。识别易受感染的个体至关重要 实施有效的治疗计划并促进良好的抗菌药物管理。该项目重点 致力于开发创新系统技术来开发基于微生物组的风险算法，该算法可识别 一般住院人群中的易感患者。正在测试的项目前提是院内 定植于肠道的病原体专门针对具有未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。我们研究中值得注意的 AMR 病原体包括 艰难梭菌、耐万古霉素肠球菌 (VRE)、耐碳青霉烯类肺炎克雷伯菌、 和产生超广谱 β-内酰胺酶的肠杆菌 (ESBL-E/CRE)，因为这些生物体 通常在引起感染之前定植于肠道。具体来说，我们表明这些优先病原体通常 共同定植缺乏关键微生物群的易感患者，这些微生物群似乎广泛存在 通过产生多种细菌素来防御这些细菌。在此 PO1 申请的项目 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 以下两个具体目标： • 目标3.1。定义代谢活跃的微生物群落结构 易感患者体内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。 这项研究具有影响力，因为我们打算建立预测微生物组风险算法以提高精确度 免疫抑制和危重患者的感染管理。长期目标是向 与风险相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 由每个人的感染引起的，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。