Biology subjects

Nigou, J.

Publications and source records attributed to Nigou, J..

5 recordsLinked to original sources

bioRxiv2026

PIM6 Induces Tolerance and Confers Protection against Mycobacterium tuberculosis in Primary Macrophages

Glycolipids are major components of the mycobacterial cell envelope and play critical roles in host-pathogen interactions. Here we investigate the capacity of the mycobacterial glycolipid phosphatidyl-myo-inositol hexamannosides (PIM6) to modulate innate responsiveness in naive primary human monocytes and monocyte-derived macrophages (MDMs). Monocytes and MDMs prestimulated with PIM6, followed by 5 days of rest, secreted attenuated levels of tumor necrosis factor alpha (TNF-), interleukin 6 (IL-6), and interleukin 10 (IL-10) following LPS challenge. PIM6 pretreatment significantly altered pattern recognition receptor expression through the experimental time course and programmed a tolerized phenotype in myeloid cells independent of TLR2 activity. In an infection challenge with H37Rv Mycobacterium tuberculosis (M.tb), MDMs pretreated with PIM6 secreted decreased levels of TNF- and IL-10 and exhibited early increased bacterial control. Together, these data reveal PIM6 as a complex immunomodulator that tolerizes myeloid cells to subsequent stimuli and exerts direct effects on the control of M.tb infection.

immunology↗

bioRxiv2026

Dynamic membrane organization coordinates protein-O-mannosylation and proteostasis in mycobacteria.

Integral membrane enzymes operate within molecular environments, yet how these are organized remains poorly understood. Using M. smegmatis as a mycobacterial model, we define the membrane environment of the protein O-mannosyltransferase MtPMT through stratified interactomics combining affinity purification-mass spectrometry under four stringencies with a persistence score. This approach resolves a persistent membrane-associated core of 108 proteins from more transient layers, revealing a hierarchically organized landscape enriched in Sec protein translocation, protein biogenesis and envelope proteostasis machineries. Reciprocal affinity purification and in vivo FRET identify YajC and FtsH as neighbors of MtPMT, while structural modelling supports integration within a Sec-associated assembly. Genetic disruption of factors reduces O-mannosylation activity, demonstrating dependence on platform integrity. The MtPMT-associated network is remodelled during growth, indicating an adaptive system. Loss of POM compromises envelope permeability and stress resilience, linking O-mannosylation to fitness. Together, our results establish protein O-mannosylation as an integrated component of a dynamic membrane platform coordinating secretion, membrane protein biogenesis and proteostasis. Our findings support a model in which mycobacterial membranes contain specialized domains dynamically modulated by physiological state.

cell biology↗

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↗

bioRxiv2021

Stimulation with mycobacterial glycolipids and PPD reveals different innate immune response profiles in active and latent TB

Upon infection with Mycobacterium tuberculosis (Mtb) the host immune response might clear the bacteria, control its growth leading to latent tuberculosis (LTB), or fail to control its growth resulting in active TB (ATB). There is however no clear understanding of the features underlying a more or less effective response. Mtb glycolipids are abundant in the bacterial cell envelope and modulate the immune response to Mtb, but the patterns of response to glycolipids are still underexplored. To identify the CD45+ leukocyte activation landscape induced by Mtb glycolipids in peripheral blood of ATB and LTB, we performed a detailed assessment of the immune response of PBMCs to the Mtb glycolipids lipoarabinomannan (LAM) and its biosynthetic precursor phosphatidyl-inositol mannoside (PIM), and PPD. At 24 h and 5 days of stimulation, cell profiling and secretome analysis was done using mass cytometry and high-multiplex immunoassay. PIM mainly affected antigen-presenting cells to produce both proinflammatory (IL-2, IL-6, IL-17A, TNF- and GM-CSF), and IL-4 and IL-10 cytokines, but not IFN-{gamma}. LAM triggered a similar, albeit weaker, response. By contrast, PPD induced an increase in IFN-{gamma}-producing cells. Moreover, PPD also led to increased numbers of IL-2, IL-6, IL-10, IL-17A, TNF- and GrzB-producing cells. Treatment with an anti-TLR2 antibody led to partial inhibition of PIM-induced IL-6 production in myeloid cells, suggesting that PIM induces IL-6 production through TLR2. Expansion of monocyte subsets in response to PIM or LAM was reduced in both ATB and LTB as compared to healthy controls, suggesting a hyporesponsive/tolerance pattern in Mtb-infected individuals.

immunology↗

bioRxiv2019

Synthetic mycobacterial molecular patterns work synergistically to recapitulate complete Freund’s adjuvant

Complete Freunds adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus trehalose dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal trehalose dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.

immunology↗