Role of peroxisome proliferator-activated receptor gamma (PPAR-γ) in Coxiella burnetii infection
Dr. Minal Mulye, Ph.D.
Medicine and Health Sciences
Peroxisome proliferator-activated receptors (PPARs) are important nuclear receptors in regulating macrophage lipid metabolism and modulating cellular inflammatory responses. In recent years, host cell PPARs have been linked to bacterial pathogenesis and macrophage infections. Specifically, bacteria-induced manipulation of lipid droplets (LD), host lipid storage organelles, are directly associated with PPAR-γ activation. For example, the intracellular pathogens Mycobacterium bovis and M. leprae breakdown the macrophage LDs to release free fatty acids. These free fatty acids subsequently activate PPAR-γ to induce an anti-inflammatory immune response, thus sustaining Mycobacterial intracellular growth. Our previously published studies report that the intracellular bacterium Coxiella burnetii induces host cell LD breakdown to support its growth in macrophages. Coxiella is known to cause non-culturable endocarditis that can present up to 20 years post initial infection, suggesting its ability to survive long-term in the host by subverting the host immune response. Our overall goal is to identify the strategies that Coxiella employs to manipulate the host immune response. This could ultimately aid in developing therapeutic targets to inhibit Coxiella’s intracellular growth. Since LD breakdown is important for intracellular Coxiella growth through the release of free fatty acids (PPAR-γ agonists), we hypothesize that Coxiella infection activates host cell PPAR-γ to induce an anti-inflammatory environment which supports bacterial growth and infection. To test this hypothesis, we quantified PPAR-γ gene expression in Coxiella-infected macrophages using quantitative Real Time PCR (qRT-PCR) at different times post-infection. Compared to uninfected cells, infected macro-phages demonstrated increased PPAR-γ gene expression suggesting that Coxiella induces PPAR-γ activation. Ongoing studies are focused on identifying PPAR-γ tran-scriptional activity in Coxiella-infected cells and the downstream targets. Future studies will determine if PPAR-γ activity is dependent on host cell LD metabolism and identify potential PPAR-γ antagonists as therapeutic targets to inhibit Coxiella intracellular growth.
Copyright 2019 all authors
Spencer, Celina OMS-2; Calhoun, Adelaide OMS-2; and Mulye, Minal Ph.D, "Role of peroxisome proliferator-activated receptor gamma (PPAR-γ) in Coxiella burnetii infection" (2019). MU-COM Research Day. 153.