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: 10226289
• 负责人: Tor C. Savidge
• 金额: $ 53.95万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226289
• 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; 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：从共生到病原体过渡的功能性微生物组和宿主签名 过度使用抗生素和细菌的适应性已导致病原体中的抗菌素耐药性（AMR） 重要的公共卫生问题。识别容易感染的人至关重要 实施有效的治疗计划并促进良好的抗菌管理。这个项目集中在 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 在医院人口中易感患者。正在测试的项目前提是医院 在肠道上定位的病原体特异性针对未成熟婴儿的肠道微生物群的个体 允许病原体定植的特征。我们研究的著名AMR PATHOGEN包括 梭状芽胞杆菌艰难梭菌，万古霉素耐药肠球菌（VRE），耐碳青霉烯氏菌的肺炎，肺炎 并扩展频谱β-内酰胺酶产生肠杆菌（ESBL-E/CRE），因为这些生物 在引起感染之前，通常会在肠道上定植。具体来说，我们表明这些优先病原体经常 共同殖民化的弱势患者，他们缺少Keystone Microbiota物种，似乎是广泛的 通过产生潜水细菌素来保护这些细菌。在此PO1应用程序的项目3中，我们将 对这些独特的宿主 - 微生物菌 - 育毒素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。定义用代谢活跃的微生物群社区结构 易感患者的病原体定植和疾病进展。 •目标3.2。表征Keystone Microbiota特征及其受保护的抗菌素 机制。 这项研究具有影响力，因为我们打算建立预测性微生物组风险算法以精确 免疫抑制和重症患者的感染管理。长期目标是建议 与风险相匹配的临床监测和治疗干预措施的医师和医疗保健利益相关者 由每个人的感染以及允许的定义的宿主 - 微生物菌相互作用所带来的 到其他新兴感染。