Biology subjects

Mathew, L.

Publications and source records attributed to Mathew, L..

4 recordsLinked to original sources

bioRxiv2026

Hypoxia drives asymmetric envelope remodelling to promote membrane adaptation and antibiotic tolerance in mycobacteria

Mycobacterium tuberculosis persists within the host by adapting to stressful microenvironments, with hypoxia representing a key clinically relevant challenge. However, how hypoxia alters mycobacterial membrane organization and function remains poorly understood. Using Mycobacterium smegmatis as a model, we combined membrane biophysics, layer-resolved lipidomics, and membrane-drug interaction analyses to characterize envelope adaptation under oxygen limitation. Hypoxia induced asymmetric remodelling of the cell envelope, with the inner membrane becoming more ordered and less hydrated, while the outer membrane exhibited increased fluidity and hydration. Lipidomic analyses revealed corresponding membrane-specific changes, including enrichment of saturated, tightly packed lipids in the inner membrane and unsaturated, inverted-conical lipids in the outer membrane. Functionally, hypoxic cells showed reduced envelope permeability and decreased susceptibility to rifampicin, while membrane partitioning studies suggested reduced rifampicin association with hypoxia-adapted inner membranes. We identify asymmetric envelope remodeling as a previously unrecognized principle of bacterial adaptation to environmental stress. Rather than responding as a uniform structure, the mycobacterial envelope undergoes coordinated but divergent remodeling in its constituent membrane layers during hypoxia. This spatially resolved response couples inner membrane rigidification with outer membrane fluidization, generating a functionally specialized envelope architecture that simultaneously preserves membrane integrity, modulates permeability, and reduces antibiotic association. These findings suggest that membrane asymmetry is not merely a structural feature of complex bacterial envelopes but an actively regulated adaptive strategy that links environmental sensing to stress resilience and antimicrobial tolerance

biophysics↗

bioRxiv2025

Remote Host Manipulation by Pathogenic Bacterial Extracellular Vesicles

Bacterial extracellular vesicles (BEVs) are known to enhance infection susceptibility in vivo, yet the mechanistic basis for this remote preconditioning of host cells is unknown. Here, we discover an evolutionarily conserved, lipid-driven physical mechanism by which pathogenic bacterial EVs systemically arrest phagosome maturation in bystander host cells. Using live-cell fluorescence lifetime imaging, in vitro reconstitution and micromanipulation, we show that EVs from diverse pathogens - Mycobacterium tuberculosis, Klebsiella pneumoniae, and Staphylococcus aureus - fuse with host plasma, phagosomal, and lysosomal membranes. This fusion increase membrane order and perturbs early phagosomal maturation. Transcriptomic profiling confirms a broad downregulation of phagosome maturation genes while upregulation of lysosomal stress responsive genes. Crucially, in vitro reconstitution shows that EVs, and their purified lipids alone, are sufficient to induce phase separation and increase membrane order, directly inhibiting phago-lysosomal fusion. Our findings establish a paradigm in which pathogens exploit EVs not merely as delivery vehicles, but as tools to remotely rewire host cell membrane mechanics to hijack phagosome maturation and promote infection - a strategy that moves beyond canonical effector-based models of pathogenesis.

cell biology↗

bioRxiv2025

Bacterial suppression of intestinal fungi via activation of human gut γδ T-cells

Gut symbionts condition mucosal immunity to resist infection by enteropathogens, but the specific microbes and mechanisms involved differ significantly between host species. In higher primates, bacterial metabolite HMB-PP is sensed by a specialized population of V{gamma}9V{delta}2+T-cells, which we now report can potently suppress growth of endogenous fungi in human intestinal organ cultures. In healthy intestine, HMB-PP-stimulated V{delta}2+T-cells restricted outgrowth of keystone fungus Candida albicans via a mechanism that required IL-22. In contrast, Crohns disease (CD) patients with reduced V{delta}2+T-cell numbers displayed outgrowth of C. albicans strains that readily formed toxin-producing filaments, triggered neutrophil extracellular traps, and induced macrophage IL-1{beta} release ex vivo. Genomic and proteomic analysis of the Candida isolates suggested increased tissue adhesion of CD-derived strains, which rapidly invaded the gut barrier in an intestine-on-a-chip model. These data reveal that bacterial activation of V{delta}2+T-cells suppresses fungal pathobionts in human gut via an IL-22-dependent mechanism that is dysregulated in CD.

immunology↗

bioRxiv2023

γδ T cells respond directly and selectively to the skin commensal yeast Malassezia for IL-17-dependent fungal control.

Stable microbial colonization of the skin depends on tight control by the host immune system. The lipid-dependent yeast Malassezia typically colonizes skin as a harmless commensal and is subject to host type 17 immunosurveillance, but this fungus has also been associated with diverse skin pathologies in both humans and animals. Using a murine model of Malassezia exposure, we show that V{gamma}4+ dermal {gamma}{delta} T cells expand rapidly and are the major source of IL-17A mediating fungal control in colonized skin. A pool of memory-like Malassezia-responsive V{gamma}4+ T cells persisted in the skin, were enriched in draining lymph nodes even after fungal clearance, and were protective upon fungal re-exposure up to several weeks later. Induction of {gamma}{delta}T17 immunity depended on IL-23 and IL-1 family cytokine signalling, whereas Toll-like and C-type lectin receptors were dispensable. Furthermore, V{gamma}4+ T cells from Malassezia-exposed hosts were able to respond directly and selectively to Malassezia-derived ligands, independently of antigen-presenting host cells. Reactivity of human {gamma}{delta} T cells against Malassezia spp. confirmed the relevance of this fungus-specific response across different host species. The fungal moieties detected were shared across diverse species of the Malassezia genus, but not conserved in other Basidiomycota or Ascomycota. These data provide novel mechanistic insight into the induction and maintenance of type 17 immunosurveillance of skin commensal colonization that has significant implications for cutaneous health. AUTHOR SUMMARYMalassezia is the most abundant fungus living on our skin and is usually harmless, but this microbe has also been shown to play a role in pathological conditions such as eczema and dermatitis. Here, we investigated how a population of V{gamma}4+ {gamma}{delta} T cells protect mouse skin against fungal overgrowth. While generally considered part of the innate immune system, we found that {gamma}{delta} T cells were maintained long after Malassezia was cleared from the skin of experimentally-infected animals. These cells displayed memory-like features and were highly efficient at fighting the fungus after a secondary challenge. We observed that classic fungal pattern recognition receptors were not involved, and that antigen-presenting cells were not required to generate Malassezia-protective {gamma}{delta} T cells. Finally, we confirmed that {gamma}{delta} T cells can recognise Malassezia, both in mice and human hosts. The fungal structure that triggers these responses was highly specific to Malassezia and was not conserved among other fungi. Our results highlight for the first time an important role for {gamma}{delta} T cells in preventing uncontrolled growth of the most abundant skin fungus. These findings have implications for several Malassezia-associated pathologies including eczema, dermatitis, and potentially even cancer.

immunology↗