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

这项资助的PI是一名医学博士，致力于学术研究，最近完成了他的临床研究 在西雅图华盛顿大学传染病系接受培训。该提案描述了一个5 年培训计划，旨在确立国际和平研究所在天然免疫领域的独立研究人员地位 对呼吸道病原体的寄主保护。 具体地说，该提案侧重于细胞内核苷酸寡聚化结构域(NOD)样的作用 NOD1和NOD2受体在检测和预防嗜肺军团菌肺炎中的作用 社区获得性肺炎的重要原因。在我们的初步研究中，我们已经表明LP能够检测到 NOD1和NOD2基因缺陷的小鼠对Lp的免疫反应发生了改变。为了确定关联性 在对LP的固有宿主免疫反应中，目标1建议确定通过什么机制 NOD1和NOD2缺乏导致整个动物的免疫反应受损。在目标2中，我们将确定 NOD1和NOD2对LP反应的细胞机制。最后，在目标3中，我们计划通过以下方式定义人类的意义 分析人类NOD1和NOD2基因变异并确定与LP肺炎的相关性 接触病原体后获得性LP肺炎。完成这些目标将使我们能够更好地理解 细胞内病原体检测在肺部肺炎中的作用可能导致 对已知疾病或改进的疫苗接种策略的个人进行免疫治疗干预。 提供给PI的资源和专业知识是唯一适合该项目的。托马斯·霍恩博士，初选 导师，是先天免疫和人类遗传学领域的专家。肖恩·斯克雷特博士拥有丰富的经验 用小鼠敲除的LP肺炎模型。这种组合特别适合于理解先天免疫。 对呼吸道病原体的反应。这项建议旨在通过增加我们对健康的了解来改善公众健康 宿主对肺部病原体的一天免疫反应有助于设计有益的干预措施，以改善结果。 相关性(见InsluctionsV 嗜肺军团菌是一种重要的肺部病原体，已知可引起肺炎的一种重要 占总人口的比例。这一建议试图确定寄主对此作出反应的机制 军团菌。了解宿主对LP的免疫应答可能会改善患者的管理 活动性LP肺炎，或未来改进的疫苗接种策略。

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 (See inslructionsV 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.