Innate Immune Response to Coxiella burnetii Infection

描述（由申请方提供）：贝氏柯克斯体是NIAID B类优先病原体和选择因子，是人畜共患病Q热的病原体。在人类中，这种发热性疾病经常通过吸入获得，其特征是肺炎，伴有慢性感染引起的严重并发症。对宿主对肺部感染C. burnetii是缺乏的，这个项目的目的是解决赤字。巨噬细胞是维持C.贝氏体感染我们已经发现了一个长期居住的肺泡巨噬细胞亚群，在感染的后期阶段和低剂量感染的早期阶段都是感染的关键部位;因此，我们假设这些巨噬细胞为维持C.贝氏体感染，并参与感染转移到宿主肝、脾和心脏。为了检验这一假设，制定了两个具体目标。第一，是由常驻肺泡巨噬细胞对宿主易感性的贡献的确定。使用亲脂性染料示踪剂将允许确定感染的细胞群。选择性消融这些细胞群将允许确定它们在宿主感染易感性中的作用。其次，我们将确定C。贝氏体从宿主肺转移到肝、脾和心脏。同样，差异染料标记和选择性消融将有助于识别和确定参与这种易位的细胞类型的相对重要性。被动转移研究将用于确定这些鉴定的细胞类型在宿主内细菌易位中的机制作用。在广泛的背景下，从这项工作中获得的知识与在人体内观察到的多种致病性疾病的研究有关。例如，结核分枝杆菌（Mycobacterium tuberculosis）和嗜肺军团菌（Legionella pneumophila），分别是结核病和军团病的病原体，是主要通过吸入获得的细胞内病原体，并存在于人巨噬细胞内。因此，研究宿主的先天免疫应答，无论是直接接触后还是在长期感染期间，都是一项重要的研究。 这是打击这些病原体威胁的重要步骤。

DESCRIPTION (provided by applicant): Coxiella burnetii, an NIAID category B priority pathogen and select agent, is the causative agent of the zoonotic disease Q fever. In humans, this febrile disease is frequently acquired via inhalation and is characterized by pneumonia with severe complications resulting from occurances of chronic infection. A clear understanding of the host innate immune response to pulmonary infections with C. burnetii is lacking and this project aims to address the deficit. It is commonly accepted that the macrophage is a key cell in sustaining C. burnetii infection. We have found a subset of long-lived resident alveolar macrophages representing a key site of infection during both later stages of infection and early stages of low dose infection; because of this, we hypothesize that these macrophages provide a required niche for the maintenance of C. burnetii infection and are involved in the translocation of infection to the host liver, spleen and heart. To test this hypothesis, two specific aims have been developed. First, is a determination of the contribution to host susceptibility by resident alveolar macrophages. The use of lipophilic dye tracers will allow determination of infected cell populations. Selective ablation of these cellular populations will then allow for the determination of their role in host susceptibility to infection. Secondly, we will determine the mechanisms by which C. burnetii translocates from the host lung to the liver, spleen and heart. Again, differential dye labeling and selective ablation will facilitate the identification and determine the relative importance of cell types involved in this translocation. Passive transfer studies will be employed to determine the mechanistic role of these identified cell types in bacterial translocation within the host. In a broad context, the knowledge acquired from this work is relevant to the study of multiple pathogenic conditions observed within humans. For example, Mycobacterium tuberculosis and Legionella pneumophila, the causative agents of tuberculosis and Legionnaires' disease respectively, are intracellular pathogens acquired predominantly through inhalation and harbored within human macrophages. Therefore, study of the host innate immune response, both directly after exposure and during protracted infection, is an important step in combating these pathogenic threats.