Dual receptor engagement by mannose-capped lipoarabinomannan reprograms macrophage lipid metabolism in tuberculosis

Necrotizing granulomas, the pathological hallmark of active tuberculosis, are characterized by the accumulation of lipid droplet-laden macrophage foam cells that contribute to tissue destruction, bacterial persistence, and transmission. Despite their central role in tuberculosis pathogenesis, the molecular mechanisms driving foam cell formation remain poorly defined. Here, we show that the mycobacterial lipoglycan mannose-capped lipoarabinomannan (ManLAM) induces macrophage lipid droplet accumulation through coordinated engagement of Toll-like receptor 2 and Dectin-2. Distinct structural moieties within ManLAM are selectively required for recognition by each receptor. Engagement of both receptors induces lipid metabolic reprogramming and enhances NF-κB-mediated inflammatory signaling, yet lipid accumulation proceeds through an mTORC1-PPARγ-dependent pathway that is largely independent of NF-κB activation. ManLAM-induced lipid metabolic changes closely mirror those elicited during <i>Mycobacterium tuberculosis</i> infection, both in neutral lipid composition and in their dependence on the mTORC1-PPARγ axis. These findings identify ManLAM as a major mycobacterial input into foam cell-associated lipid metabolism and establish ligand-level coordination of innate receptor engagement as a mechanism linking mycobacterial recognition to macrophage lipid metabolic reprogramming.