Assessing Klebsiella pneumoniae invasion of the intact gut microbiome

评估肺炎克雷伯菌对完整肠道微生物组的入侵

• 批准号: 10780120
• 负责人: Jay Vornhagen
• 金额: $ 24.88万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10780120
• 关键词: 16S ribosomal RNA sequencing; Address; Antibiotic Resistance; Antibiotics; Bacteremia; Bacteria; Bacterial Physiology; Biological Assay; Categories; Cells; Citrate (si)-Synthase; Clinic; Complement; Data; Development; Disease; Ecology; Extended-spectrum β-lactamase; Foundational Skills; Health; Hospitals; Human; In Vitro; Indigenous; Infection; Inflammation; Invaded; Investigation; Klebsiella pneumoniae; Knowledge; Libraries; Life; Mediating; Mentors; Metabolic; Michigan; Mission; Nosocomial pneumonia; Operon; Pathogenesis; Patients; Physiological; Pneumonia; Population; Process; Production; Public Health; Publications; Research; Resistance; Risk; Role; Stress; System; Tellurium; Testing; Therapeutic; Therapeutic Intervention; Training; United States National Institutes of Health; Universities; Urinary tract infection; Work; antibiotic resistant infections; antimicrobial peptide; biological adaptation to stress; carbapenemase; density; design; enhancing factor; fitness; gut colonization; gut microbes; gut microbiome; gut microbiota; host microbiota; infection risk; inflammatory milieu; innovation; member; microbial; microbial composition; microbial host; microbiome; microbiota; mouse model; novel; novel diagnostics; novel therapeutics; pathogen; prevent; resilience; response; stress resilience; stress tolerance; therapeutic development; therapeutic target; therapy design; transposon sequencing

Project summary/abstract The bacteria Klebsiella pneumoniae is an important cause of hospital-acquired and antibiotic-resistant infections, including pneumonia, bacteremia, and urinary tract infection. Infection risk sharply increases when K. pneumoniae is present in the gut, and K. pneumoniae must overcome many barriers to successfully colonize the gut, including the gut microbiome. While disruption of the gut microbiome through antibiotics can permit colonization, K. pneumoniae frequently colonizes the gut in the absence of antibiotics when an intact microbiome is present. There is a fundamental gap in our understanding of how K. pneumoniae invades the intact gut microbiome. Furthermore, the specific mechanisms underlying the ability of K. pneumoniae to compete with the endogenous gut microbiota remain unexplored. The objective of this proposal is to identify and characterize factors necessary for K. pneumoniae gut colonization in an intact gut microbiome and determine how these factors influence K. pneumoniae fitness in the gut. The central hypothesis of this proposal is that Kp employs microbiome dependent and specific factors to enhance their ability to directly compete with the host microbiota or survive microbiota-mediated modulation of host inflammation to invade the intact gut microbiome, which is critical for Kp gut colonization. I will test this hypothesis in three specific aims: 1) define the role of a previously identified gut fitness factor, the tellurium resistance (ter) operon during invasion of an intact gut microbiome; 2) determine the role of the ter operon in response to physiologically relevant stresses and; 3) systematically identify K. pneumoniae fitness factors during invasion of intact gut microbiomes. The work in this proposal is innovative, as it requires the development of novel transposon sequencing application, and it addresses a gap in understanding that can shift the current paradigm of K. pneumoniae gut colonization. Completion of this work will have sustained positive impact through the identification, characterization, and prioritization of K. pneumoniae factors necessary for invasion of the intact gut microbiome, which will help guide the development of therapeutics targeted at the disruption of K. pneumoniae gut colonization. Finally, the research in this proposal is complemented by a comprehensive training plan designed to develop a foundational skillset for the pursuit of research focused on mechanisms of bacterial pathogenesis directly informed by and applicable to the clinic. This project will be undertaken within the University of Michigan in conjunction with a distinguished team of co- mentors. This team of co-mentors will complement that candidate's expertise in host-pathogen interaction by providing training in microbial ecology, exploration of bacterial physiology, and comprehensive analyses of host- microbial systems necessary for the candidate's transition to independence. These state-of-the-art studies will lead to the identification and characterization of K. pneumoniae factors that permit the invasion of the intact gut microbiome and the corresponding role of the microbiota in this process to enable the design of therapies to reduce the impact of K. pneumoniae disease.

项目摘要/摘要 肺炎细菌是导致医院获得和抗生素耐药性感染的重要原因， 包括肺炎，菌血症和尿路感染。当K时，感染风险急剧增加。 肺炎存在于肠道中，而K.肺炎必须克服许多成功殖民的障碍 肠道，包括肠道微生物组。虽然通过抗生素破坏肠道微生物组可以允许 殖民化，K。肺炎经常在没有抗生素的情况下在完整的微生物组时定居肠道 在场。我们对K.肺炎如何入侵完整的肠有根本的差距 微生物组。此外，肺炎与肺炎竞争能力的具体机制 内源性肠道微生物群仍未开发。该提议的目的是识别和表征 完整肠道微生物组中肺炎肺炎的肠道肠道定殖所需的因素，并确定这些如何 因素影响肠道中的肺炎。该提议的中心假设是KP采用 微生物组依赖性和特定因素，以增强其直接与宿主菌群竞争的能力 或生存的微生物群介导的宿主炎症调节以侵入完整的肠道微生物组，这是 对于KP肠道定殖至关重要。我将以三个特定目的测试该假设：1）定义先前的作用 鉴定出肠道适应性因子，在完整的肠道微生物组侵袭过程中，胎耐耐药性（TER）操纵子； 2） 确定TER操纵子在生理相关应力方面的作用； 3）系统识别 在完整的肠道微生物组侵袭过程中，K。肺炎适应性因子。该提案中的工作是创新的， 因为它需要开发新型的转座子测序应用，并且可以解决 理解可以改变肺炎肠肠肠球菌的当前范式。完成这项工作 通过K.的识别，表征和优先级，将持续积极影响。 入侵完整肠道微生物组所需的肺炎因素，这将有助于指导发展 旨在破坏肺炎肠道肠道定殖的治疗剂。最后，该提案的研究 旨在发展基础技能的全面培训计划的补充 研究的重点是直接告知并适用于诊所的细菌发病机理的机制。这 项目将在密歇根大学与一个杰出的共同团队一起进行 导师。该团队将补充候选人通过 提供微生物生态学培训，细菌生理学的探索以及宿主的全面分析 - 候选人向独立过渡所必需的微生物系统。这些最先进的研究将 导致允许侵入完整肠道的肺炎K.肺炎因子的鉴定和表征 微生物组和微生物群在此过程中的相应作用，使疗法的设计达到 减少肺炎链球菌疾病的影响。