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

描述（由申请人提供）：本资助的PI是一名医学博士，博士他致力于学术研究，最近在西雅图的华盛顿大学传染病系完成了临床培训。该提案描述了一项为期5年的培训计划，旨在将PI确立为宿主对呼吸道病原体保护的先天免疫领域的独立研究者。具体而言，该提案集中在细胞内核苷酸寡聚化结构域（NOD）样受体Nod1和Nod2在检测嗜肺军团菌（Lp）肺炎（社区获得性肺炎的重要原因）和预防嗜肺军团菌（Lp）肺炎中的作用。在我们的初步研究中，我们已经表明Lp能够检测Lp，并且Nod1和Nod2缺陷的小鼠改变了对Lp的免疫应答。为了确定Nodl和Nod2在对Lp的先天宿主免疫应答中的相关性，目的1提出确定Nodl和Nod2缺陷导致整个动物中免疫应答受损的机制。目的2：确定Nod1和Nod2对Lp应答的细胞机制。最后，在目标3中，我们计划通过分析Nod1和Nod2中的人类遗传变异性来定义人类意义，并在暴露于病原体后获得Lp肺炎的患者队列中确定与Lp肺炎的关联。这些目标的完成将允许更好地理解细胞内病原体检测在肺肺炎中的作用，可能导致对患有已知疾病的个体的免疫干预或改进的疫苗接种策略的发展。PI拥有的资源和专业知识非常适合该项目。主要导师托马斯霍恩博士是先天免疫和人类遗传学领域的专家。Shawn Skerrett博士在Lp肺炎的小鼠敲除模型方面具有丰富的经验。这种组合特别适合于理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肺部病原体的宿主免疫反应的知识来改善公共卫生，以便有一天帮助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，已知可在相当大比例的人群中引起肺炎。该建议旨在确定宿主对这种军团菌的反应机制。了解宿主对Lp的免疫应答可能会改善活动性Lp肺炎的患者管理，或改善未来的疫苗接种策略。

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.