Biology subjects

Vehra, O.

Publications and source records attributed to Vehra, O..

2 recordsLinked to original sources

bioRxiv2026

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

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.

microbiology↗

bioRxiv2025

Mycobacterium tuberculosis effector protein PE5 hijacks the host CRL2 ubiquitin ligase complex

Mycobacterium tuberculosis (Mtb) is the leading infectious killer and infects one quarter of the global population. During infection, Mtb evade host immune responses via secreted effector proteins that interfere with, modulate, and protect from potent antibacterial responses. One such class of mycobacterial effector proteins are the PE/PPE proteins, a huge family of proteins encoded by an impressive 10% of the Mtb genome. Because some PE/PPEs have demonstrated roles in immune regulation and host cell interaction, and because of the sheer number of PE/PPEs in pathogenic mycobacteria ([~]170-200+ members depending on the species), they are thought to contribute to Mtb virulence and pathogenesis. However, the cellular functions of Mtbs 169 PE/PPE proteins have yet to be comprehensively characterized, at least in part because of their high GC content and large regions of extremely repetitive regions found both in DNA and amino acid sequences. One member of this family, PE5, is likely critical for mycobacterial pathogenesis, but its cellular and molecular functions, particularly within a host cell, are unexplored. We investigated the molecular functions of PE5 using affinity purification coupled mass spectrometry (AP-MS) and identified an interaction with the CRL2 complex, a host E3 ubiquitin ligase complex. PE5 interacts with CRL2 through its C-terminal Gly-Gly motif, which is bound by the CRL2 substrate receptor, KLHDC2. PE5 does not get ubiquitinated, but it is degraded upon being bound by KLHDC2. Interestingly, binding to PE5 increases the autoubiquitination of KLHDC2, but this autoubiquitination does not interfere with KLHDC2s ability to degrade known substrates or the ability of CRL2 to degrade substrates bound by other substrate receptors. Therefore, while PE5 binds to CRL2-KLHDC2 and does not get ubiquitinated itself, it does not appear to impede CRL2 activity. This study identifies a novel interaction between PE5 and a host ubiquitin ligase pathway, and it raises new questions about how PE5s interaction with the host modulates cell biology to promote Mtb virulence. Furthermore, it implicates CRL2 complexes in mediating cell-intrinsic host response to Mtb infection, a novel function for this ubiquitin ligase complex. Our results expand our understanding of how PE/PPEs may target innate immune responses and contribute to our knowledge of how uncharacterized PE/PPEs contribute to Mtbs virulence.

microbiology↗