Q fever is an emerging zoonotic disease caused by the intracellular bacteria, Coxiella burnetii. Acute disease presents as a flu-like illness however in rare cases can progress into to a chronic disease that commonly manifests as endocarditis. Inhalation is the most common route of infection in the United States with an ID50 of fewer than 10 organisms. After inhalation, C. burnetii is phagocytosed by alveolar macrophages where it is trafficked through the phagolysosomal pathway. Upon fusion with lysosomes, the type IV secretion system is activated and begins to secrete effectors to manipulate host processes and generate the replication niche known as the parasitophorous vacuole. Previous studies have shown C. burnetii modulation of host apoptosis and autophagy pathways. While autophagy was originally considered a homeostatic process of organelle recycling, it has recently been shown to be an important host response for clearing invading pathogens and modulating inflammatory responses. Due to the intracellular nature of C. burnetii, we hypothesized that autophagy was utilized for nutrient acquisition. The target host cell type for C. burnetii are macrophages, which are potent innate immune cells that utilize autophagy and are responsible for clearance of foreign particles. Therefore, in this dissertation we focus specifically on autophagy in macrophages or macrophage-like cells. We show that autophagosomes are actively recruited to the PV via the T4SS. Early interactions with autophagosomes are dispensable for infection, however autophagic flux is not induced. Assessing autophagic flux interested us in the protein p62, which is a cargo receptor responsible for targeting specific substrates for degradation via autophagy. Indeed, we see p62 is also recruited to the PV in a T4SS-dependent manner and co-localizes with LC3 at the PV. Our studies of p62 led us to examine two pathways modulated by p62; inflammasome regulation and the Nrf2-Keap1 pathway. Preliminary data indicates p62 may be responsible for degradation of inflammasome complexes during virulent C. burnetii infection but not during avirulent infection. We see that the Nrf2-Keap1 pathway is activated during C. burnetii infection by stabilization of Nrf2 and localization of Nrf2 to the nuclei of infected cells. Additionally, we see stabilization of p62 during starvation-mediated autophagy, a hallmark of the Nrf2- Keap1 pathway. Collectively, these studies provide insight to manipulation of autophagy by C. burnetii and additionally provide a new pathway for study during bacterial infections, the Nrf2-Keap1 pathway.
|Commitee:||Blevins, Jon, Forrest, Craig, Post, Stephen, Stumhofer, Jason|
|School:||University of Arkansas for Medical Sciences|
|Department:||Microbiology and Immunology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Keywords:||Autophagy, Coxiella burnetii, Macrophages|
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