Granulysin antimicrobial activity promotes dormancy in Mycobacterium tuberculosis

Schmidiger, S.; McCaffrey, E. F.; Schmidt, J. M.; Abdul Hameed, O.; Mpina, M.; Tumbo, A.; Mfinanga, E.; Haraka, F.; Hiza, H.; Sasamalo, M.; Hella, J.; Walch, M.; Fellay, J.; Gagneux, S.; Reither, K.; Carballido, J. M.; Arbues, A.; Portevin, D.

doi:10.1101/2024.09.27.615427

bioRxiv · 10.1101/2024.09.27.615427

Granulysin antimicrobial activity promotes dormancy in Mycobacterium tuberculosis

Schmidiger, S.·McCaffrey, E. F.·Schmidt, J. M.·Abdul Hameed, O.·Mpina, M.·Tumbo, A.·Mfinanga, E.·Haraka, F.·Hiza, H.·Sasamalo, M.·Hella, J.·Walch, M.·Fellay, J.·Gagneux, S.·Reither, K.·Carballido, J. M.·Arbues, A.·Portevin, D.

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Abstract

Human tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat. Granulomas constitute a hallmark of TB pathogenesis that can clear, contain or exacerbate an infection. Containment is exploited by Mtb as a hideout to persist in a dormant, antibiotic-tolerant state only to resuscitate upon immunosuppression. The immune determinants of a granulomatous response driving Mtb persistence remain elusive. We here combined an ex vivo granuloma model with peripheral blood mononuclear cell (PBMC) specimens from TB patients and a high-dimensional mass cytometry (CyTOF) approach to shed light on the immune factors prompting Mtb dormancy. Compared to healthy controls, patient-derived ex vivo granulomas rapidly force Mtb to adopt a dormant-like state; an observation that correlates with the presence of activated innate (-like) cytotoxic lymphocytes. We further demonstrate that Mtb dormancy is induced by direct exposure to granulysin, thereby unravelling an immune escape mechanism to cytotoxic lymphocyte activity.

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Schmidiger, S., McCaffrey, E. F., Schmidt, J. M., Abdul Hameed, O., Mpina, M., Tumbo, A., Mfinanga, E., Haraka, F., Hiza, H., Sasamalo, M., Hella, J., Walch, M., Fellay, J., Gagneux, S., Reither, K., Carballido, J. M., Arbues, A., Portevin, D.. 2024-09-30. Granulysin antimicrobial activity promotes dormancy in Mycobacterium tuberculosis. https://doi.org/10.1101/2024.09.27.615427

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