Event Title
Role of lipid droplets and prostaglandinE2 in Coxiella burnetii intracellular growth
Location
Philadelphia, PA
Start Date
11-5-2022 1:00 PM
End Date
11-5-2022 4:00 PM
Description
The obligate intracellular bacterium Coxiella burnetii causes potentially fatal endocarditis several years after initial infection suggesting the bacterium’s ability to persist long-term in the host. Our overall goal is to determine the mechanisms Coxiella employs for its long-term intracellular survival. While the bacterium initially infects alveolar macrophages, in endocarditis patients Coxiella is found in foamy macrophages rich in neutral lipid storage organelles called lipid droplets (LDs). Our previous studies show that Coxiella manipulates host LD metabolism via the Type 4 Secretion System (T4SS), a major virulence factor which secretes bacterial effector proteins into the host cell cytoplasm to manipulate cellular processes. Additionally, blocking LD breakdown almost completely inhibits bacterial growth suggesting that LD-derived lipids are critical for Coxiella intracellular survival. LD breakdown releases arachidonic acids, precursors for the lipid immune mediator prostaglandin E2 (PGE2) which promotes an immunosuppressive environment in alveolar macrophages. We hypothesize that Coxiella manipulates host cell LD metabolism to promote a PGE2-mediated immunosuppressive environment and survive long-term in the host. To test this, we quantified gene expression of PGE2 synthesis enzyme cyclooxygenase-2 (cox-2) in Coxiella-infected alveolar macrophages. Compared to uninfected cells, cox-2 was upregulated in Coxiella-infected but not T4SS mutant-infected macrophages. ELISA showed Coxiella-dependent increase in PGE2 levels indicating that Coxiella T4SS actively manipulates cox-2 expression resulting in increased PGE2 production. Further, blocking PGE2 production using FDA-approved COX-2 inhibitors significantly decreased Coxiella intracellular growth suggesting the importance of PGE2 during Coxiella infection. Ongoing studies are identifying the direct correlation between LDs and PGE2 production and the contribution of LDs to immunosuppression during Coxiella infection. Future studies will determine the potential of blocking PGE2 production as a supplemental therapy for Coxiella endocarditis.
Embargo Period
5-26-2022
Role of lipid droplets and prostaglandinE2 in Coxiella burnetii intracellular growth
Philadelphia, PA
The obligate intracellular bacterium Coxiella burnetii causes potentially fatal endocarditis several years after initial infection suggesting the bacterium’s ability to persist long-term in the host. Our overall goal is to determine the mechanisms Coxiella employs for its long-term intracellular survival. While the bacterium initially infects alveolar macrophages, in endocarditis patients Coxiella is found in foamy macrophages rich in neutral lipid storage organelles called lipid droplets (LDs). Our previous studies show that Coxiella manipulates host LD metabolism via the Type 4 Secretion System (T4SS), a major virulence factor which secretes bacterial effector proteins into the host cell cytoplasm to manipulate cellular processes. Additionally, blocking LD breakdown almost completely inhibits bacterial growth suggesting that LD-derived lipids are critical for Coxiella intracellular survival. LD breakdown releases arachidonic acids, precursors for the lipid immune mediator prostaglandin E2 (PGE2) which promotes an immunosuppressive environment in alveolar macrophages. We hypothesize that Coxiella manipulates host cell LD metabolism to promote a PGE2-mediated immunosuppressive environment and survive long-term in the host. To test this, we quantified gene expression of PGE2 synthesis enzyme cyclooxygenase-2 (cox-2) in Coxiella-infected alveolar macrophages. Compared to uninfected cells, cox-2 was upregulated in Coxiella-infected but not T4SS mutant-infected macrophages. ELISA showed Coxiella-dependent increase in PGE2 levels indicating that Coxiella T4SS actively manipulates cox-2 expression resulting in increased PGE2 production. Further, blocking PGE2 production using FDA-approved COX-2 inhibitors significantly decreased Coxiella intracellular growth suggesting the importance of PGE2 during Coxiella infection. Ongoing studies are identifying the direct correlation between LDs and PGE2 production and the contribution of LDs to immunosuppression during Coxiella infection. Future studies will determine the potential of blocking PGE2 production as a supplemental therapy for Coxiella endocarditis.
Comments
Winner of PCOM Philadelphia Division of Research Staff Award