Coxiella burnetii is the intracellular bacterial agent of human Q fever, a debilitating flu-like illness that can also present as severe chronic endocarditis. C. burnetii is spread by contaminated aerosols and targets alveolar phagocytes in vivo, where the pathogen actively regulates vesicular trafficking to establish a phagolysosome-like parasitophorous vacuole (PV) in which to replicate. Although PV biogenesis is critical for infection, the macrophage innate immune response to infection is not fully understood. The current proposal uses two novel infection models, human lung tissue and alveolar macrophages, to test the hypothesis that C. burnetii specifically alters human alveolar macrophage physiology to prevent inflammasome activity and avoid the innate immune response. These models will provide human-specific information not obtainable using current animal models.
Aim 1 will characterize C. burnetii infection of lung cells, definitively proving the cell type targeted during human infection.
Aim 2 will define macrophage inflammasome activation in response to avirulent C. burnetii and identify mechanisms by which virulent organisms avoid detection. Collectively, these studies will provide enhanced modeling of the C. burnetii infectious process and the human innate immune response to pulmonary pathogens.
Coxiella burnetii is an intracellular bacterial pathogen that causes the zoonosis human Q fever, a debilitating acute disease that can present as chronic endocarditis. Currently, C. burnetii virulence determinants are poorly understood and the human innate immune response to infection has not been fully addressed. Characterization of two novel infection models will provide better understanding of intracellular sensing components involved in detecting the pathogen. The goals of the proposed research are to 1) define C. burnetii infection of human lung cells and 2) define virulent C. burnetii prevention of the innate immune response.
| Shaw, Edward I; Voth, Daniel E (2018) Coxiella burnetii: A Pathogenic Intracellular Acidophile. Microbiology : |
| Winchell, Caylin G; Dragan, Amanda L; Brann, Katelynn R et al. (2018) Coxiella burnetii Subverts p62/Sequestosome 1 and Activates Nrf2 Signaling in Human Macrophages. Infect Immun 86: |
