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-{kappa}B-mediated inflammatory signaling, yet lipid accumulation proceeds through an mTORC1-PPAR{gamma}-dependent pathway that is largely independent of NF-{kappa}B activation. ManLAM-induced lipid metabolic changes closely mirror those elicited during Mycobacterium tuberculosis infection, both in neutral lipid composition and in their dependence on the mTORC1-PPAR{gamma} 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. Significance statementCharacterizing how lipid-laden foam cells form is central to understanding tuberculosis pathogenesis because foam cells define the necrotizing lesions that drive lung damage and transmission. We show that a single mycobacterial component uses distinct structural features to engage two innate immune receptors on macrophages and induce lipid metabolic remodeling and foam cell formation. This finding establishes the principle that microbial ligand architecture can encode engagement of multiple receptors to shape host responses. These insights provide a mechanistic framework for tuberculosis pathogenesis and identify host pathways that may represent targets for host-directed intervention.