The University of Southampton
University of Southampton Institutional Repository

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

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.
2399-3642
Ahmed, Mohamed
9d82d448-7f08-4304-a5d2-b8cf12317353
Mackenzie, Jared
f0352cab-ab6a-40e0-98b6-970b09e9b854
Tezera, Liku Bekele
c5598dbf-23a8-4934-96a4-7c783bf9e776
Krause, Robert
c8a1efd5-d86e-4f39-a8d0-c37820f30389
Truebody, Barry
dd6f5637-19bb-425a-82b6-2a273710f7ae
Garay Baquero, Diana
da9136fe-3d47-4d04-8ab3-96bfe17a773c
Vallejo Pulido, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Govender, Katya
b626d75a-1ecf-4b82-8cda-7cf51f19c987
Adamson, John
b80c4942-809d-4a94-942c-36c1cf3ae8d9
Fisher, Hayden
160b3dea-4f68-4638-b2a3-48757c0efd73
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Steyn, Adrie J. C.
3ef8af2e-cb97-49bb-83ad-a4d128d55097
Leslie, Alasdair
84d4f578-f3c0-46cc-9c83-a8d9bb40c38c
Ahmed, Mohamed
9d82d448-7f08-4304-a5d2-b8cf12317353
Mackenzie, Jared
f0352cab-ab6a-40e0-98b6-970b09e9b854
Tezera, Liku Bekele
c5598dbf-23a8-4934-96a4-7c783bf9e776
Krause, Robert
c8a1efd5-d86e-4f39-a8d0-c37820f30389
Truebody, Barry
dd6f5637-19bb-425a-82b6-2a273710f7ae
Garay Baquero, Diana
da9136fe-3d47-4d04-8ab3-96bfe17a773c
Vallejo Pulido, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Govender, Katya
b626d75a-1ecf-4b82-8cda-7cf51f19c987
Adamson, John
b80c4942-809d-4a94-942c-36c1cf3ae8d9
Fisher, Hayden
160b3dea-4f68-4638-b2a3-48757c0efd73
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Steyn, Adrie J. C.
3ef8af2e-cb97-49bb-83ad-a4d128d55097
Leslie, Alasdair
84d4f578-f3c0-46cc-9c83-a8d9bb40c38c

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).

Record type: Article

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 - Version of Record
Available under License Creative Commons Attribution.
Download (2MB)

More information

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).

Identifiers

Local EPrints ID: 473488
URI: http://eprints.soton.ac.uk/id/eprint/473488
ISSN: 2399-3642
PURE UUID: 6cb82b42-c153-409a-b6ce-baa3536f9152
ORCID for Liku Bekele Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for Diana Garay Baquero: ORCID iD orcid.org/0000-0002-9450-8504
ORCID for Andres Vallejo Pulido: ORCID iD orcid.org/0000-0002-4688-0598
ORCID for Hayden Fisher: ORCID iD orcid.org/0000-0003-0093-0921
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613

Catalogue record

Date deposited: 20 Jan 2023 17:46
Last modified: 17 Mar 2024 03:54

Export record

Altmetrics

Contributors

Author: Mohamed Ahmed
Author: Jared Mackenzie
Author: Robert Krause
Author: Barry Truebody
Author: Diana Garay Baquero ORCID iD
Author: Andres Vallejo Pulido ORCID iD
Author: Katya Govender
Author: John Adamson
Author: Hayden Fisher ORCID iD
Author: Salah Mansour ORCID iD
Author: Paul Elkington ORCID iD
Author: Adrie J. C. Steyn
Author: Alasdair Leslie

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×