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: 10462499
• 负责人: Jay Vornhagen
• 金额: $ 5.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462499
• 关键词: 16S ribosomal RNA sequencing; Address; Antibiotic Resistance; Antibiotics; Bacteremia; Bacteria; Bacterial Physiology; Biological Assay; Cells; Centers for Disease Control and Prevention (U.S.); Citrate (si)-Synthase; Clinic; Complement; Data; Development; Disease; Ecology; Extended-spectrum β-lactamase; Foundations; 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.

项目总结/文摘

项目成果

A structured professional development curriculum for postdoctoral fellows leads to recognized knowledge growth.

• DOI: 10.1371/journal.pone.0260212
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Steen K;Vornhagen J;Weinberg ZY;Boulanger-Bertolus J;Rao A;Gardner ME;Subramanian S
• 通讯作者: Subramanian S