Role of Lipid Droplets in Prostaglandin E2 Production During Coxiella Burnetii Infection
Coxiella burnetii is an obligate intracellular bacterial pathogen and causative agent of Q fever. Chronic Q-fever manifests as potentially fatal endocarditis weeks to years after initial infection, suggesting Coxiella’s ability to live long-term inside the host. Our overall goal is to understand Coxiella’s long-term survival mechanisms. While Coxiella initially infects alveolar macrophages, it's also found in lipid droplet (LD)-containing foamy macrophages in cardiac valves of endocarditis patients. Our previous studies show Coxiella manipulates LD homeostasis via the Type 4 Secretion System (T4SS), a major virulence factor which secretes bacterial effector proteins into the host cell cytoplasm to manipulate cell processes. Further, inhibiting LD breakdown almost completely blocks bacterial growth. Since LD breakdown releases lipids, our data suggests LD-derived lipids are critical for Coxiella survival. LD breakdown releases arachidonic acid, a precursor of prostaglandin E2 (PGE2), which promotes an immunosuppressive environment in alveolar macrophages. Hence we hypothesize Coxiella achieves long-term intracellular survival by manipulating host cell LD metabolism to establish a PGE2-mediated immunosuppressive environment. To test this hypothesis, we quantified gene expression of PGE2 synthesis enzyme cyclooxygenase-2 (cox-2) in differentially infected alveolar macrophages. Compared to uninfected cells, cox-2 was upregulated in Coxiella-infected macrophages but not T4SS mutant-infected cells. Further, quantitation by ELISA showed increased PGE2 levels in Coxiella-infected cells compared to uninfected cells. These studies indicate Coxiella T4SS actively manipulates cox-2 expression thus resulting in increased PGE2 in Coxiella-infected cells. Ongoing studies are identifying the direct correlation between LDs and PGE2 production in Coxiella-infected cells. Future studies will determine the potential of blocking PGE2 as a supplemental therapy for Coxiella endocarditis.
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"Role of Lipid Droplets in Prostaglandin E2 Production During Coxiella Burnetii Infection" (2018). MU-COM Research Day. 91.