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.

项目概要 该职业发展提案描述了一个为期 5 年的指导研究项目，该项目将增强 我们对肺炎克雷伯菌 (Kp) 在肺部发病机制和随后宿主免疫的了解 回复。该项目将建立在候选人的细菌学、革兰氏阴性菌发病机制的背景之上。 阴性微生物和传染病。教学和实践培训相结合，详细信息请参见 全面的职业发展计划，将为候选人提供增强的肺训练 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，例如 流式细胞术和 ChIP-Seq。 成功完成拟议目标将使候选人获得 确保独立资金和过渡为独立医师科学家所需的技能。 候选人将受益于医学博士 David A. Hunstad 和 John P. Atkinson 的出色指导， 医学博士。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 革兰氏阴性细菌感染中的相互作用和宿主免疫反应，而阿特金森博士是一位世界级的专家 著名免疫学家，在培训医师科学家方面拥有丰富的经验。该候选人获得支持 由世界一流的咨询委员会选出，每位成员均具有与研究相关的特定专业知识 提案和职业发展计划。这项工作将在宏伟的华盛顿大学进行 拥有丰富的科学资源和培养医师科学家的悠久历史的环境。 Kp 感染，包括肺炎、尿路感染和血流感染，发病率急剧上升 住院病人的增加； CDC 最近宣布 Kp 和其他碳青霉烯类感染 耐药肠杆菌科 (CRE) 的威胁级别为紧急。两个重要的 Kp 毒力因子， 已知荚膜和 1 型菌毛在不同的宿主生态位中很重要，特别是肺和泌尿道， 分别。考生将检验以下假设：这些毒力因子是协调且相反的 监管，并将确定该监管背后的机制联系。候选人将决定如何 1 型菌毛、它们的相开关 fimS、调节器 FimK 和细菌第二信使 cyclo-di-GMP 影响 Kp 肺炎小鼠模型中 Kp 胶囊的产生和下游毒力。 此外，尽管 Kp 很普遍且具有临床重要性，但人们对天然保护作用知之甚少。 对 Kp 的免疫力。使用 Kp 的新模型应变，候选者的初步数据表明 Kp 小鼠肺部感染可以保护其免受后续感染。淋巴细胞浸润类似 在这些受保护宿主的肺部观察到可诱导的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 胶囊引起保护。这些研究可能会识别出适合抗毒力的细菌靶标 疗法，同时也为预防严重 Kp 感染的潜在疫苗开发奠定了基础。