Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

Abstract Acute infection of the central nervous system is one of the deadliest diseases, but the mechanisms by which intracellular bacteria infiltrate the brain remain poorly understood. Phagocytic cells are usually recognized as the battlefield on which war is waged against intracellular bacteria; however, little is known about how the intracellular bacteria take advantage of infected phagocytes to access the brain. In this study, we find that a novel CD36 + foamy macrophage subpopulation participates in penetration of the brain by intracellular bacteria. Biomechanical analysis reveals that abundant protrusions and adhesion molecules on foamy macrophages confer significant resistance to the mechanical stress of blood flow, thereby providing more opportunities for these macrophages to adhere to the vascular endothelial surface during neuroinvasion. Through metabolomics analysis, we find that macrophage lipid metabolism is recalibrated during bacterial neuroinvasion, and that β-hydroxybutyrate promotes the formation and survival of CD36 + foamy macrophages. Taken together, our findings uncover a pathway by which intracellular bacteria hijack macrophages to invade the brain, suggesting that lipid metabolism might play a role in the prevention or resolution of bacterial neuroinvasion.