Mycobacterium tuberculosis senses host Interferon-γ via the membrane protein MmpL10
Mycobacterium tuberculosis senses host Interferon-γ via the membrane protein MmpL10
Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens. Several cytokines are known to increase virulence of bacterial pathogens, leading us to investigate whether Interferon-γ (IFN-γ), a central regulator of the immune defense against Mtb, has a direct effect on the bacteria. We found that recombinant and T-cell derived IFN-γ rapidly induced a dose-dependent increase in the oxygen consumption rate (OCR) of Mtb, consistent with increased bacterial respiration. This was not observed in attenuated Bacillus Calmette–Guérin (BCG), and did not occur for other cytokines tested, including TNF-α. IFN-γ binds to the cell surface of intact Mtb, but not BCG. Mass spectrometry identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner of IFN-γ, supported by molecular modelling studies. IFN-γ binding and the OCR response was absent in Mtb Δmmpl10 strain and restored by complementation with wildtype mmpl10. RNA-sequencing and RT-PCR of Mtb exposed to IFN-γ revealed a distinct transcriptional profile, including genes involved in virulence. In a 3D granuloma model, IFN-γ promoted Mtb growth, which was lost in the Mtb Δmmpl10 strain and restored by complementation, supporting the involvement of MmpL10 in the response to IFN-γ. Finally, IFN-γ addition resulted in sterilization of Mtb cultures treated with isoniazid, indicating clearance of phenotypically resistant bacteria that persist in the presence of drug alone. Together our data are the first description of a 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.
Ahmed, Mohamed
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Mackenzie, Jared
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Tezera, Liku Bekele
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Krause, Robert
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Truebody, Barry
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Garay Baquero, Diana
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Vallejo Pulido, Andres
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Govender, Katya
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Adamson, John
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Fisher, Hayden
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Essex, Jonathan W.
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Mansour, Salah
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Elkington, Paul
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Steyn, Adrie J. C.
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Leslie, Alasdair
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1 December 2022
Ahmed, Mohamed
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Mackenzie, Jared
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Tezera, Liku Bekele
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Krause, Robert
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Truebody, Barry
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Garay Baquero, Diana
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Vallejo Pulido, Andres
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Govender, Katya
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Adamson, John
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Fisher, Hayden
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Essex, Jonathan W.
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Mansour, Salah
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Elkington, Paul
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Steyn, Adrie J. C.
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Leslie, Alasdair
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Ahmed, Mohamed, Mackenzie, Jared, Tezera, Liku Bekele, Krause, Robert, Truebody, Barry, Garay Baquero, Diana, Vallejo Pulido, Andres, Govender, Katya, Adamson, John, Fisher, Hayden, Essex, Jonathan W., Mansour, Salah, Elkington, Paul, Steyn, Adrie J. C. and Leslie, Alasdair
(2022)
Mycobacterium tuberculosis senses host Interferon-γ via the membrane protein MmpL10.
Communications Biology, 5 (1317), [1317].
(doi:10.1038/s42003-022-04265-0).
Abstract
Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens. Several cytokines are known to increase virulence of bacterial pathogens, leading us to investigate whether Interferon-γ (IFN-γ), a central regulator of the immune defense against Mtb, has a direct effect on the bacteria. We found that recombinant and T-cell derived IFN-γ rapidly induced a dose-dependent increase in the oxygen consumption rate (OCR) of Mtb, consistent with increased bacterial respiration. This was not observed in attenuated Bacillus Calmette–Guérin (BCG), and did not occur for other cytokines tested, including TNF-α. IFN-γ binds to the cell surface of intact Mtb, but not BCG. Mass spectrometry identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner of IFN-γ, supported by molecular modelling studies. IFN-γ binding and the OCR response was absent in Mtb Δmmpl10 strain and restored by complementation with wildtype mmpl10. RNA-sequencing and RT-PCR of Mtb exposed to IFN-γ revealed a distinct transcriptional profile, including genes involved in virulence. In a 3D granuloma model, IFN-γ promoted Mtb growth, which was lost in the Mtb Δmmpl10 strain and restored by complementation, supporting the involvement of MmpL10 in the response to IFN-γ. Finally, IFN-γ addition resulted in sterilization of Mtb cultures treated with isoniazid, indicating clearance of phenotypically resistant bacteria that persist in the presence of drug alone. Together our data are the first description of a 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.
Text
s42003-022-04265-0
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Accepted/In Press date: 15 November 2022
Published date: 1 December 2022
Additional Information:
We are grateful to Dr. James Millard (AHRI) for providing clinical isolates and Dr. David Johnston of the Biomedical Imaging Unit (University of Southampton) for assistance with confocal imaging. Our thanks to Dr. Amanda Ardain for proofreading the manuscript. M.A. is supported by Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative [grant # DEL-15-006]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust [grant # 107752/Z/15/Z] and the UK government. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Wellcome Trust or the UK government. J.W.E. is supported by Cancer Research UK (A30681), S.M. is supported by Medical Research Council UK (MR/S024220/1), P.E. is supported by Medical Research Council UK (MR/P023754/1, MR/N006631/1, MR/W025728/1), A.J.C.S. is supported by National Institutes of Health (R01AI134810), A.L. is supported by Wellcome Trust, Senior Research Fellowship (210662/Z/18/Z), Wellcome Strategic Core Award (201433/A/16/A), Medical Research Council, Global Challenges Research Fund (MR/P023754/1).
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Local EPrints ID: 473488
URI: http://eprints.soton.ac.uk/id/eprint/473488
ISSN: 2399-3642
PURE UUID: 6cb82b42-c153-409a-b6ce-baa3536f9152
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Date deposited: 20 Jan 2023 17:46
Last modified: 17 Mar 2024 03:54
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Contributors
Author:
Mohamed Ahmed
Author:
Jared Mackenzie
Author:
Robert Krause
Author:
Barry Truebody
Author:
Diana Garay Baquero
Author:
Andres Vallejo Pulido
Author:
Katya Govender
Author:
John Adamson
Author:
Hayden Fisher
Author:
Adrie J. C. Steyn
Author:
Alasdair Leslie
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