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 and remains a leading cause of death from infectious disease. Interferon-γ (IFN-γ) 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-γ has a direct effect on Mtb. We found that both 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 also observed in clinical strains, but not in the vaccine strain 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, whilst TNF-α binds to neither. Mass spectrometry analysis identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner. Consistent with this, IFN-γ binding and the OCR response was absent in a Mtb Δmmpl10 strain and restored by complementation of the mutant strain. RNA-sequencing of IFN-γ exposed Mtb revealed a distinct transcriptional profile, including genes involved in virulence and cholesterol catabolism. Finally, exposure of Mtb cells to IFN-γ 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 Summary IFN-γ 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.
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 and remains a leading cause of death from infectious disease. Interferon-γ (IFN-γ) 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-γ has a direct effect on Mtb. We found that both 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 also observed in clinical strains, but not in the vaccine strain 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, whilst TNF-α binds to neither. Mass spectrometry analysis identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner. Consistent with this, IFN-γ binding and the OCR response was absent in a Mtb Δmmpl10 strain and restored by complementation of the mutant strain. RNA-sequencing of IFN-γ exposed Mtb revealed a distinct transcriptional profile, including genes involved in virulence and cholesterol catabolism. Finally, exposure of Mtb cells to IFN-γ 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 Summary IFN-γ 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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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: 471192
URI: http://eprints.soton.ac.uk/id/eprint/471192
ISSN: 2399-3642
PURE UUID: a9837e7f-908a-40d1-8d85-43750483e3d6
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Date deposited: 31 Oct 2022 17:42
Last modified: 23 Aug 2024 01:57
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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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