Multidrug-resistant bacterial pathogens pose an increasing threat to human health. Certain bacteria, such as Staphylococcus aureus, are able to survive within professional phagocytes to escape the bactericidal effects of antibiotics and evade killing by immune cells, potentially leading to chronic or persistent infections. By investigating the macrophage response to S. aureus infection, we may devise a strategy to prime the innate immune system to eliminate the infected bacteria. Here we applied untargeted tandem mass spectrometry to characterize the lipidome alteration in S. aureus infected J774A.1 macrophage cells at multiple time points. Linoleic acid (LA) metabolism and sphingolipid metabolism pathways were found to be two major perturbed pathways upon S. aureus infection. The subsequent validation has shown that sphingolipid metabolism suppression impaired macrophage phagocytosis and enhanced intracellular bacteria survival. Meanwhile LA metabolism activation significantly reduced intracellular S. aureus survival without affecting the phagocytic capacity of the macrophage. Furthermore, exogenous LA treatment also exhibited significant bacterial load reduction in multiple organs in a mouse bacteremia model. Two mechanisms are proposed to be involved in this progress: exogenous LA supplement increases downstream metabolites that partially contribute to LA's capacity of intracellular bacteria-killing and LA induces intracellular reactive oxygen species (ROS) generation through an electron transport chain pathway in multiple immune cell lines, which further increases the capacity of killing intracellular bacteria. Collectively, our findings not only have characterized specific lipid pathways associated with the function of macrophages but also demonstrated that exogenous LA addition may activate lipid modulator-mediated innate immunity as a potential therapy for bacterial infections.

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