Innate Immune Response to Coxiella burnetii Infection

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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.