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Mechanopathology of biofilm-like Mycobacterium tuberculosis cords

ABSTRACT: Mycobacterium tuberculosis (Mtb) cultured in the absence of detergent forms biofilm-like cords, a clinical identifier of virulence. Using lung-on-chip and mouse infection models, we show that cord growth in alveolar cells contributes to the suppression of innate immune signalling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. These “mechanopathological” mechanisms explain the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of WT Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of stable cords that maintain structural integrity despite mechanical perturbation. Moreover, bacteria in cords remain translationally active despite prolonged antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics of cord architectures and their functional roles in tuberculosis infection and therapy, independent of mechanisms ascribed to single bacteria.

ORGANISM(S): Mus musculus

PROVIDER: GSE238102 | GEO | 2023/11/01

REPOSITORIES: GEO

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