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bioRxiv · 10.64898/2026.02.18.706227

Synergistic activation of TLR2 and Dectin-2 by mannose-capped lipoarabinomannan reprograms macrophage lipid metabolism in tuberculosis

Nag, D.·Radeny, J.·Cui, J.·Vehra, O.·Yu, Y.·Nigou, J.·Bell, S. L.·Gennaro, M. L.
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Abstract

How innate immune receptors integrate signals from complex microbial ligands remains poorly understood, yet this integration may offer new avenues for host-directed therapies. Here, we show that the architecture of a single pathogen-derived component can organize the coordinated engagement of multiple pattern-recognition receptors to reprogram host cell behavior. We find that the mycobacterial lipoglycan mannose-capped lipoarabinomannan (ManLAM) uses distinct structural features to engage two pattern-recognition receptors, Toll-like receptor 2 (TLR2) and Dectin-2, thereby driving macrophage lipid remodeling and lipid droplet accumulation, a process linked to foam cell formation and necrotizing lesion development in tuberculosis. Dual receptor engagement also potentiates NF-{kappa}B-dependent inflammatory signaling, while lipid droplet accumulation proceeds through an mTORC1-PPAR{gamma}-dependent pathway that is largely independent of NF-{kappa}B activation, indicating that metabolic and inflammatory programs are mechanistically separable. ManLAM-induced lipid remodeling closely mirrors that induced by Mycobacterium tuberculosis infection in both neutral lipid composition and pathway dependence. In contrast, other mycobacterial ligands that are lipogenic in vitro do not measurably contribute to lipid droplet accumulation during infection. These findings identify ManLAM as a major mycobacterial driver of lipid remodeling associated with foam cell formation and establish ligand architecture as a mechanism by which complex microbial ligands organize multi-receptor signaling to direct distinct host cell programs. Significance statementOur findings establish the principle that the architecture of a single microbial ligand can organize the co-engagement of multiple innate immune receptors to shape host cell responses. Using the mycobacterial lipoglycan mannose-capped lipoarabinomannan as a model, we show that distinct structural features within a single microbial component coordinate the co-engagement of TLR2 and Dectin-2 to reprogram macrophage lipid metabolism and promote lipid droplet formation, a process linked to foam cell formation and necrotizing tuberculosis lesions. These results identify a mechanism by which complex microbial ligands can integrate host sensing pathways through their molecular structure. By defining the receptor-signaling axes that control foam cell formation, this work highlights host pathways as candidate targets for host-directed intervention.

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Nag, D., Radeny, J., Cui, J., Vehra, O., Yu, Y., Nigou, J., Bell, S. L., Gennaro, M. L.. 2026-02-18. Synergistic activation of TLR2 and Dectin-2 by mannose-capped lipoarabinomannan reprograms macrophage lipid metabolism in tuberculosis. https://doi.org/10.64898/2026.02.18.706227

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