Role of cyclooxygenase inhibitors in blocking Coxiella burnetii intracellular growth
Dr. Minal Mulye, Ph.D.
Medicine and Health Sciences
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, which can be fatal if untreated. Even for those receiving treatment, the mortality rate is 19%. Further the treatment has several restrictions and poses significant side effects. Hence, designing better treatments is crucial. To this end, it is important to determine the pathogenesis of Coxiella endocarditis. The occurrence of Coxiella endocarditis several years after initial infection suggests that the bacterium survives long term by subverting host immune response. Our overall goal is to elucidate the specific host immune pathways Coxiella modulates to achieve long-term intracellular survival and identify potential therapeutic targets. Previous studies in endocarditis patients demonstrated an increase in lipid immune mediator prostaglandin E2 (PGE2) which contributed to immunosuppression and promoted bacterial growth suggesting PGE2 importance in Coxiella survival. Our preliminary ELISAs in Coxiella-infected mouse alveolar macrophages demonstrated increased PGE2 production. Since PGE2 production directly correlates to the enzyme cyclooxygenase (Cox) expression and activity, we determined expression of constitutive Cox-1 and inducible Cox-2 genes. Compared to uninfected cells, our gene expression analysis revealed Cox-2 but not Cox-1 upregulation in Coxiellainfected alveolar macrophages. Hence, we hypothesize that inhibition of Cox-2 activity blocks Coxiella intracellular growth. To test this, we are currently treating Coxiellainfected 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 celecoxib and aspirin-treated cells. Ongoing studies are quantifying changes in Coxiella growth after celecoxib and aspirin treatment. Future studies will elucidate the mechanisms Coxiella employs to regulate Cox-2 expression and PGE2 production to induce immunosuppression.
Copyright 2019 all authors
Wooten, Steven; Kim, Constantine OMS-2; Shain, Michael OMS-2; Harrison, Morgan E. OMS-3; and Mulye, Minal Ph.D, "Role of cyclooxygenase inhibitors in blocking Coxiella burnetii intracellular growth" (2019). MU-COM Research Day. 111.