Decoding Coxiella burnetii’s immune evasion strategy: Host lipid droplets, prostaglandin E2 and PPARs 3857

Description The obligate intracellular bacterium Coxiella burnetii is transmitted to humans via inhalation which can lead to chronic endocarditis years after initial infection. This demonstrates the bacterium’s ability to survive long-term. While the host pathways Coxiella targets remain unknown, we have shown that it manipulates alveolar macrophage lipid storage organelles, called lipid droplets (LDs). LD breakdown is essential for bacterial growth and releases precursors for the immunosuppressive lipid immune mediator prostaglandin E2 (PGE2). LD breakdown-mediated PGE2 production is crucial for Coxiella intracellular survival, but whether Coxiella targets host transcriptional regulation to mediate this is not known. Peroxisome proliferator-activated receptors (PPARs) are transcription factors important for macrophage LD metabolism and immune modulation. We hypothesize that host PPARs play a key role in Coxiella intracellular survival. To test this, we measured bacterial growth in cells treated with PPAR α, β/δ, and γ subtype-specific agonists and antagonists. Altering PPARα and β/δ activity decreased Coxiella growth. Blocking PPARα activity reduced host LD numbers and PGE2 concentrations, suggesting PPARα promotes PGE2-mediated immunosuppression and Coxiella survival. Our study establishes the role of host PPARs, specifically PPARα, during Coxiella infection. Future studies will explore PPARs as potential therapeutic targets to inhibit Coxiella intracellular growth.