VIRULENCE REGULATION AND PROTECTIVE IMMUNITY IN KLEBSIELLA PNEUMONIA

肺炎克雷伯菌的毒力调节和保护性免疫

• 批准号: 9385544
• 负责人: David A. Rosen
• 金额: $ 17.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385544
• 关键词: Advisory Committees; Affect; Antibiotic Resistance; Antibiotics; Antigens; Attenuated; B-Lymphocytes; Bacteria; Bacteriology; Binding; Bronchus-Associated Lymphoid Tissue; C-terminal; Cell Lineage; Cells; Centers for Disease Control and Prevention (U.S.); ChIP-seq; Cleaved cell; Clinical; Communicable Diseases; Data; Development Plans; Enterobacteriaceae Infections; Environment; Flow Cytometry; Foundations; Funding; Gene Expression; Goals; Gram-Negative Bacterial Infections; Health; Helix-Turn-Helix Motifs; Hospitals; Human; Immune response; Immunity; Immunization; Immunobiology; Immunologist; Infection; Interleukin-17; Klebsiella; Klebsiella pneumonia bacterium; Link; Lung; Lymphocytic Infiltrate; Lymphoid; Measures; Mentors; Mentorship; Methodology; Modeling; Mus; N-terminal; Nature; Nosocomial pneumonia; Organism; Pathogenesis; Patients; Periodicity; Phagocytosis; Phase; Physicians; Pilum; Plasmids; Pneumonia; Positioning Attribute; Prevalence; Primary Infection; Process; Production; Recording of previous events; Regulation; Regulator Genes; Reproducibility; Research; Research Project Grants; Research Proposals; Resistance; Resources; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Second Messenger Systems; Secure; Sepsis; Serotyping; Signal Transduction; Site; Specific qualifier value; Survivors; System; T-Lymphocyte; Testing; Therapeutic; Training; Universities; Urinary tract; Urinary tract infection; Virulence; Virulence Factors; Washington; Work; adaptive immune response; adaptive immunity; capsule; carbapenem-resistant Enterobacteriaceae; carbapenemase; career; career development; cell type; combat; experience; experimental study; fighting; human disease; insight; intraperitoneal; killings; member; mortality; mouse model; mutant; novel therapeutic intervention; novel therapeutics; novel vaccines; pathogen; pre-clinical; prevent; promoter; protective effect; response; sensor; skills; vaccine development

PROJECT SUMMARY This career development proposal describes a 5-year mentored research project which will enhance our understanding of Klebsiella pneumoniae (Kp) pathogenesis in the lung and subsequent host immune response. The project will build upon the candidate's background in bacteriology, pathogenesis of Gram- negative organisms, and infectious diseases. A combination of didactic and practical training, detailed in the comprehensive career development plan, will provide the candidate with enhanced training in lung immunobiology, adaptive immunity, and bacterial signaling, and technical training in methodologies such as flow cytometry and ChIP-Seq. Successful completion of the proposed aims will enable the candidate to gain the skills required to secure independent funding and transition as an independent physician-scientist. The candidate will benefit from the superb mentorship of David A. Hunstad, MD, and John P. Atkinson, MD. In established and newly created murine models, Dr. Hunstad has extensively dissected host-pathogen interactions and host immune responses in Gram-negative bacterial infections, while Dr. Atkinson is a world- renowned immunologist with extensive experience in training physician-scientists. The candidate is supported by a world-class advisory committee, each member chosen for specific expertise relevant to the research proposal and career development plan. The work will take place in the tremendous Washington University environment with its abundant scientific resources and rich history in the training of physician-scientists. Kp infections, including pneumonia, urinary tract infection, and bloodstream infection, are sharply on the rise in hospitalized patients; CDC has recently declared that infections with Kp and other carbapenem- resistant Enterobacteriaceae (CRE) demand a threat level of urgent. Two important Kp virulence factors, capsule and type 1 pili, are known to be important in distinct host niches, specifically the lung and urinary tract, respectively. The candidate will test the hypothesis that these virulence factors are coordinately and inversely regulated, and will identify the mechanistic link underlying this regulation. The candidate will determine how type 1 pili, their phase switch fimS, regulator FimK, and the bacterial second messenger cyclic-di-GMP affect capsule production in Kp and downstream virulence in a murine model of Kp pneumonia. In addition, despite the prevalence and clinical importance of Kp, little is known about natural protective immunity against Kp. Using a new model strain of Kp, the candidate's preliminary data indicate that Kp infection of the lungs in mice is protective from subsequent infection. Lymphocytic infiltrates resembling inducible bronchus-associated lymphoid tissue are observed in the lungs of these protected hosts. Thus, the proposed research will also characterize the adaptive immune response to Kp pneumonia and the role of capsule in eliciting protection.These studies may identify bacterial targets amenable to anti-virulence therapeutics, while also laying the foundation for potential vaccine development to prevent serious Kp infection.

项目摘要 这个职业发展建议描述了一个为期5年的指导研究项目，将提高 我们对肺炎克雷伯氏菌（Kp）在肺中的发病机制以及随后的宿主免疫的理解 反应该项目将建立在候选人在细菌学，革兰氏菌的发病机制， 阴性微生物和传染病。教学和实践培训相结合，详细信息见 全面的职业发展计划，将为候选人提供强化培训， 免疫生物学、适应性免疫和细菌信号传导，以及方法学方面的技术培训， 流式细胞术和ChIP-Seq. 成功完成拟议目标将使候选人获得 所需的技能，以确保独立的资金和过渡作为一个独立的医生，科学家。 候选人将受益于大卫A的出色指导。Hunstad医学博士和John P. Atkinson， 马里兰州在已建立和新创建的小鼠模型中，Hunstad博士广泛剖析了宿主-病原体 革兰氏阴性菌感染的相互作用和宿主免疫反应，而阿特金森博士是一个世界- 著名的免疫学家，在培养医学科学家方面有着丰富的经验。候选人得到支持 由一个世界级的咨询委员会，每个成员选择的具体专业知识相关的研究 提案和职业发展计划。这项工作将在巨大的华盛顿大学进行 环境，其丰富的科学资源和丰富的历史，在培养医生科学家。 Kp感染，包括肺炎，尿路感染和血液感染， 住院患者的增加; CDC最近宣布，感染Kp和其他碳青霉烯- 耐药肠杆菌科（CRE）要求紧急威胁级别。两个重要的Kp毒力因子， 被膜和1型皮利，已知在不同的宿主生态位中是重要的，特别是肺和泌尿道， 分别候选人将检验这些毒力因子协同和反向作用的假设 监管，并将确定这种监管的机制联系。候选人将决定如何 1型皮利、它们的相位转换fimS、调节因子FimK和细菌第二信使cyclic-di-GMP影响 Kp肺炎小鼠模型中Kp的荚膜产生和下游毒力。 此外，尽管Kp的流行和临床重要性，但对天然保护作用知之甚少。 对Kp免疫。使用Kp的新模式菌株，候选人的初步数据表明，Kp 小鼠肺部感染可保护小鼠免受随后的感染。淋巴细胞浸润样 在这些受保护宿主的肺中观察到诱导型支气管相关淋巴组织。因此 拟议的研究还将描述对Kp肺炎的适应性免疫反应以及 这些研究可能会确定细菌的目标服从抗病力 治疗，同时也为潜在的疫苗开发奠定基础，以防止严重的Kp感染。