PPARα modulation of lipid metabolism alters host defense and Staphylococcus aureus virulence during superinfection 2309857

Abstract Introduction Secondary bacterial superinfections following influenza remain a critical driver of respiratory mortality, particularly when caused by MRSA. While bioactive lipids are known regulators of inflammation, the molecular mechanisms linking lipid metabolism to compromised host defense remain incompletely understood. We investigated the role of PPARα, a nuclear receptor that regulates fatty acid oxidation, in shaping innate immune dysfunction during superinfection. Methods To investigate cellular mechanisms, hMDM and primary human neutrophils were treated with PPARα agonists and antagonists, followed by infection with MRSA. The accumulation of lipid droplets (LD) and the phagocytic activity were quantified using fluorescence microscopy. Additionally, to examine the in vivo transcriptional landscapes, single-cell RNA sequencing was performed on innate immune cells isolated from superinfected C57BL/6 mice, in comparison to PPARα-deficient (Ppara−/−) mice. Results Our research identifies a signaling pathway involving CYP450 and PPARα, in which eicosanoids induced by influenza trigger abnormal activation of PPARα. This creates a metabolic trade-off: the increased biogenesis of LD significantly suppresses phagocytosis and the ability to kill bacteria. We demonstrated that this lipid sequestration driven by PPARα diverts metabolic resources, which effectively impairs phagocytes and increases the burden of MRSA. Additionally, scRNA sequencing revealed a shift from pro-inflammatory to anti-inflammatory programs in wild-type mice compared to Ppara-/- mice, highlighting PPARα as a key factor contributing to susceptibility. Conclusion Collectively, these findings demonstrate that CYP450-mediated activation of PPARα functionally disrupts the neutrophil/monocyte axis by prioritizing lipid storage over pathogen elimination. Targeting this immunometabolic switch offers a novel therapeutic strategy to restore phagocytic competency and alleviate the severity of post-viral bacterial pneumonia. Funding Source N/A Topic Categories Mucosal and Regional Immunology (MUC)