Event Title
Role of cyclooxygenase inhibitors in blocking Coxiella burnetii intracellular growth.
Location
Philadelphia, PA
Start Date
10-5-2021 12:00 AM
End Date
13-5-2021 12:00 AM
Description
Coxiella burnetii is an obligate intracellular bacterial pathogen and a causative agent of culture-negative endocarditis. While Coxiella initially infects alveolar macrophages, it may disseminate and cause endocarditis up to 20 years after initial infection. If untreated, Coxiella endocarditis can be fatal. Even with the current, several month long doxycycline and hydroxychloroquine treatment regimen, the mortality rate is 19%. Further, the drugs have several contraindications, and prolonged use poses significant side effects. Hence, designing better treatment alternatives is crucial. To this end, it is important to understand the pathogenesis of Coxiella endocarditis. The occurrence of endocarditis several years after initial infection suggests that Coxiella successfully subverts the host immune response. Our overall goal is to elucidate the specific host immune pathways Coxiella modulates to facilitate long-term intracellular survival and identify potential therapeutic targets. Previous studies in endocarditis patients demonstrated that increased lipid immune mediator prostaglandin E2 (PGE2) levels contribute to immunosuppression and promote Coxiella growth. Our preliminary studies show increased PGE2 production in Coxiella-infected mouse alveolar macrophages suggesting PGE2 importance in Coxiella pathogenesis and intracellular survival. Since PGE2 production directly correlates to the enzyme cyclooxygenase (Cox) expression and activity, we measured the expression of constitutive Cox-1 and inducible Cox-2 genes. Compared to uninfected cells, Cox-2 but not Cox-1 was upregulated in Coxiella-infected alveolar macrophages. Hence, we hypothesize that inhibition of Cox-2 activity blocks Coxiella intracellular growth. To test this we are currently treating Coxiella-infected cells with FDA-approved Cox-2 inhibitor celecoxib and pan-Cox inhibitor aspirin. Compared to untreated cells, our preliminary qualitative microscopic analysis suggests Coxiella growth inhibition in aspirin-treated cells. Ongoing studies are quantifying changes in Coxiella growth with celecoxib treatment. Future studies will elucidate the mechanisms Coxiella employs to regulate Cox-2 expression and PGE2 production to induce immunosuppression.
Embargo Period
6-14-2021
Role of cyclooxygenase inhibitors in blocking Coxiella burnetii intracellular growth.
Philadelphia, PA
Coxiella burnetii is an obligate intracellular bacterial pathogen and a causative agent of culture-negative endocarditis. While Coxiella initially infects alveolar macrophages, it may disseminate and cause endocarditis up to 20 years after initial infection. If untreated, Coxiella endocarditis can be fatal. Even with the current, several month long doxycycline and hydroxychloroquine treatment regimen, the mortality rate is 19%. Further, the drugs have several contraindications, and prolonged use poses significant side effects. Hence, designing better treatment alternatives is crucial. To this end, it is important to understand the pathogenesis of Coxiella endocarditis. The occurrence of endocarditis several years after initial infection suggests that Coxiella successfully subverts the host immune response. Our overall goal is to elucidate the specific host immune pathways Coxiella modulates to facilitate long-term intracellular survival and identify potential therapeutic targets. Previous studies in endocarditis patients demonstrated that increased lipid immune mediator prostaglandin E2 (PGE2) levels contribute to immunosuppression and promote Coxiella growth. Our preliminary studies show increased PGE2 production in Coxiella-infected mouse alveolar macrophages suggesting PGE2 importance in Coxiella pathogenesis and intracellular survival. Since PGE2 production directly correlates to the enzyme cyclooxygenase (Cox) expression and activity, we measured the expression of constitutive Cox-1 and inducible Cox-2 genes. Compared to uninfected cells, Cox-2 but not Cox-1 was upregulated in Coxiella-infected alveolar macrophages. Hence, we hypothesize that inhibition of Cox-2 activity blocks Coxiella intracellular growth. To test this we are currently treating Coxiella-infected cells with FDA-approved Cox-2 inhibitor celecoxib and pan-Cox inhibitor aspirin. Compared to untreated cells, our preliminary qualitative microscopic analysis suggests Coxiella growth inhibition in aspirin-treated cells. Ongoing studies are quantifying changes in Coxiella growth with celecoxib treatment. Future studies will elucidate the mechanisms Coxiella employs to regulate Cox-2 expression and PGE2 production to induce immunosuppression.