Mycobacterium tuberculosis senses host Interferon- gamma via the membrane protein MmpL10

Ahmed, M.; Mackenzie, J. S.; Krause, R.; Truebody, B.; Tezera, L. B.; Garay-Baquero, D.; Vallejo, A. F.; Govender, K.; Adamson, J.; Elkington, P.; Steyn, A. J. C.; Leslie, A.

doi:10.1101/2021.11.12.468344

bioRxiv · 10.1101/2021.11.12.468344

Mycobacterium tuberculosis senses host Interferon- gamma via the membrane protein MmpL10

Ahmed, M.·Mackenzie, J. S.·Krause, R.·Truebody, B.·Tezera, L. B.·Garay-Baquero, D.·Vallejo, A. F.·Govender, K.·Adamson, J.·Elkington, P.·Steyn, A. J. C.·Leslie, A.

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Abstract

Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens and remains a leading cause of death from infectious disease. Interferon-{gamma} (IFN-{gamma}) is a central regulator of the immune defense against Mtb. Several cytokines have been shown to increase virulence of other bacterial pathogens, leading us to investigate whether IFN-{gamma} has a direct effect on Mtb. We found that both recombinant and T-cell derived IFN-{gamma} rapidly induced a dose-dependent increase in the oxygen consumption rate (OCR) of Mtb, consistent with increased bacterial respiration. This was also observed in clinical strains, but not in the vaccine strain Bacillus Calmette-Guerin (BCG), and did not occur for other cytokines tested, including TNF-. IFN-{gamma} binds to the cell surface of intact Mtb, but not BCG, whilst TNF- binds to neither. Mass spectrometry analysis identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner. Consistent with this, IFN-{gamma} binding and the OCR response was absent in a Mtb {Delta}mmpl10 strain and restored by complementation of the mutant strain. RNA-sequencing of IFN-{gamma} exposed Mtb revealed a distinct transcriptional profile, including genes involved in virulence and cholesterol catabolism. Finally, exposure of Mtb cells to IFN-{gamma} resulted in sterilization of bacilli treated with isoniazid (INH), indicating clearance of phenotypically resistant bacteria that persist in the presence of INH alone. Our data suggest a novel mechanism allowing Mtb to respond to host immune activation that may be important in the immunopathogenesis of TB and have use in novel eradication strategies. One-Sentence SummaryIFN-{gamma} is a critical component of effective immune defense in human tuberculosis yet its causative agent, Mycobacterium tuberculosis it able to sense this cytokine and increase virulence and respiration in response.

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Ahmed, M., Mackenzie, J. S., Krause, R., Truebody, B., Tezera, L. B., Garay-Baquero, D., Vallejo, A. F., Govender, K., Adamson, J., Elkington, P., Steyn, A. J. C., Leslie, A.. 2021-11-12. Mycobacterium tuberculosis senses host Interferon- gamma via the membrane protein MmpL10. https://doi.org/10.1101/2021.11.12.468344

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