The Role of Nod1 and Nod2 in the Pathogeneisis of Legionella Pneumophila Pneumoni

Nod1和Nod2在嗜肺军团菌发病机制中的作用

• 批准号: 8069242
• 负责人: William Richard Berrington
• 金额: $ 13.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069242
• 关键词: Aerosols; Animals; Antigens; Binding; Clinical; Commit; Communicable Diseases; Communities; Detection; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Exposure to; Family; Future; Genetic Predisposition to Disease; Grant; Host Defense; Human; Human Genetics; Immune; Immune response; Immunosuppressive Agents; Immunotherapeutic agent; In Vitro; Individual; Intervention; Knockout Mice; Knowledge; Lead; Legionella; Legionella pneumophila; Lung; Lung diseases; Mastigophora; Mentors; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Nucleotides; Organism; Outcome; Pathogen detection; Patients; Pattern; Phagolysosome; Pharmaceutical Preparations; Pneumonia; Population; Public Health; Research; Research Personnel; Resources; Risk Factors; Role; Severity of illness; Smoker; Toll-like receptors; Training; Training Programs; Universities; Washington; Water Supply; cohort; design; detector; experience; improved; in vivo; leucine-rich repeat protein; macrophage; microbial; mortality; pathogen; receptor; respiratory; response; retinal rods; vaccination strategy

DESCRIPTION (provided by applicant): The PI of this grant is an M.D., Ph.D. who is committed to academic research and recently completed his clinical training in the Division of Infectious Disease at the University of Washington in Seattle. The proposal describes a 5 year training program designed to establish the PI as an independent researcher in the field of innate immunity in the host protection to respiratory pathogens. Specifically, the proposal is focused on the role of intracellular Nucleotide Oligermerization Domain (NOD)-like receptors, Nodi and Nod2, in the detection of and protection from Legionella pneumophila (Lp) pneumonia, an important cause of community acquired pneumonia. In our preliminary studies we have shown that Lp is able to detect Lp, and that mice deficient in Nodi and Nod2 have altered immune responses to Lp. In order to determine the relevance of Nodi and Nod2 in the innate host immune response to Lp, Aim 1 proposes to determine the mechanisms by which Nodi and Nod2 deficiency lead to impaired inmiune responses in the whole animal. In Aim 2, we willdetermine the cellular mechanism of the Nodi and Nod2 response to Lp. Lastly, in Aim 3 we plan to define human significance by analyzing human genetic variability in Nodi and Nod2 and identify association to Lp pneumonia in a cohort of patients acquired Lp pneumonia following exposure to the pathogen. Completion of these aims will allow for better unstanding of the role of intracellular pathogen detection in pulmonary pneumonias possibly leading to development of immunotherapeutic interventions to individuals with known disease or improved vaccination strategies. The resources and expertise made available to the PI is uniquely suited for the project. Dr Thomas Hawn, the primary mentor, is an expert in the fields of innate immunity and human genetics. Dr. Shawn Skerrett has extensive experience with mouse knockout models of Lp pneumonia. The combination is uniquely suited to understanding innate immune responses to respiratory pathogens. This proposal seeks to improve public health by increasing our knowledge of the host immune response to pulmonary pathogens to one day help design beneficial interventions to improve outcome. RELEVANCE: Legionella pneumophila is an important lung pathogen, known to cause pneumonia in a significant proportion of the population. This proposal seeks to identify the mechanism of the host repsonse to this Legionella. Understanding the host immune resposne to Lp may lead to improved patient management of active Lp pneumonia, or to improved vaccination strategies in the future.

描述（由申请人提供）：本次资助的PI是医学博士、博士。他致力于学术研究，最近在西雅图华盛顿大学传染病科完成了临床培训。该提案描述了一项为期 5 年的培训计划，旨在使 PI 成为宿主对呼吸道病原体保护的先天免疫领域的独立研究员。具体来说，该提案的重点是细胞内核苷酸寡聚化结构域 (NOD) 样受体 Nodi 和 Nod2 在检测和预防嗜肺军团菌 (Lp) 肺炎（社区获得性肺炎的重要原因）中的作用。在我们的初步研究中，我们表明 Lp 能够检测 Lp，并且缺乏 Nodi 和 Nod2 的小鼠改变了对 Lp 的免疫反应。为了确定 Nodi 和 Nod2 在宿主对 Lp 的先天免疫反应中的相关性，目标 1 建议确定 Nodi 和 Nod2 缺陷导致整个动物免疫反应受损的机制。在目标 2 中，我们将确定 Nodi 和 Nod2 对 Lp 反应的细胞机制。最后，在目标 3 中，我们计划通过分析 Nodi 和 Nod2 的人类遗传变异来定义人类意义，并在暴露于病原体后感染 Lp 肺炎的一组患者中确定与 Lp 肺炎的关联。这些目标的完成将有助于更好地了解细胞内病原体检测在肺部肺炎中的作用，可能导致对患有已知疾病的个体开发免疫治疗干预措施或改进疫苗接种策略。提供给 PI 的资源和专业知识非常适合该项目。首席导师 Thomas Hawn 博士是先天免疫和人类遗传学领域的专家。 Shawn Skerrett 博士在 Lp 肺炎小鼠敲除模型方面拥有丰富的经验。该组合特别适合了解对呼吸道病原体的先天免疫反应。该提案旨在通过增加我们对宿主对肺部病原体的免疫反应的了解来改善公共卫生，有一天有助于设计有益的干预措施来改善结果。 相关性：嗜肺军团菌是一种重要的肺部病原体，已知会在相当一部分人群中引起肺炎。该提案旨在确定宿主对该军团菌的反应机制。了解宿主对 Lp 的免疫反应可能会改善活动性 Lp 肺炎的患者管理，或改善未来的疫苗接种策略。