Mycobacterium tuberculosis micro-diversity promotes intra-macrophagic persistence and antibiotic tolerance

BioRxiv : the Preprint Server for Biology
Charlotte Genestet on behalf of the Lyon TB study group


Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptive response during tuberculosis (TB) development and provide insights to anti-TB treatment response. Here, we investigated the genetic micro-diversity of persistent clinical Mtb isolates and its dynamics during controlled stress experiments chosen to mimic the course of TB disease. A minor variant characterized by a modified lipid profile, became enriched during stress experiments. The variant was found to be associated with drug-tolerance involving efflux pumps deregulation and with intracellular persistence subsequent to phagolysosome avoidance and autophagy decrease. Furthermore, pharmacological modeling predicted increased risk of treatment failure for isolates enriched in the former variant. Even under extreme experimental conditions, the diversity in variants was always maintained, suggesting a strong functional complementarity between variants of the Mtb bacterial population during disease dynamics. Such diversity may be responsible of Mtb adaptation to its host and play a role along the successive steps leading to multi-drug resistant TB. Altogether, our findings support the fact that Mtb micro-diversity shoul...Continue Reading

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