Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

Acute infection of the central nervous system is one of the most lethal diseases, yet the mechanisms by which intracellular bacteria infiltrate the brain remain poorly understood. Phagocytic cells are typically regarded as the primary site of conflict in the battle against intracellular bacteria; however, little is known about how the intracellular bacteria exploit infected phagocytes to gain access to the brain. In this study, we show that a novel CD36+ Fabp4+ Pparg+ macrophage subpopulation (CD36+macrophage) participates in penetration of the brain by intracellular bacteria without disruption of the blood-brain barrier. Biomechanical analysis reveals that the abundance of protrusions and adhesion molecules on CD36+ macrophages confers significant resistance to the mechanical stress of blood flow, thereby providing increased opportunities for these macrophages to adhere to the vascular endothelial surface. Metabolomics analysis identifies that macrophage lipid metabolism is dysregulated during bacterial neuroinvasion, and that {beta}-hydroxybutyrate promotes the formation and survival of CD36+ macrophages. Importantly, ketogenesis exacerbates symptoms during bacterial neuroinvasion, which could be halted by supplementing with physiological levels of glucose. Collectively, our findings elucidate a pathway by which intracellular bacteria hijack macrophages to invade the brain, suggesting that glycolipid metabolic homeostasis may play a role in the prevention or resolution of bacterial neuroinvasion. Highlights1. Intracellular bacteria hijack CD36+ M{varphi} for brain invasion without disrupting the BBB 2. CD36+ M{varphi} has enhanced adhesion to BMECs and increased resistance to shear flow 3. Ketogenesis promotes bacterial neuroinvasion that can be halted by glucose treatment 4. Accumulation of peripheral BHB and CD36+ M{varphi} fuels bacterial neuroinvasion in humans O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/582462v4_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@19fe27org.highwire.dtl.DTLVardef@7cf218org.highwire.dtl.DTLVardef@fa0d16org.highwire.dtl.DTLVardef@71366b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG