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- Title
Mycobacterium tuberculosis senses host Interferon-γ via the membrane protein MmpL10.
- Authors
Ahmed, Mohamed; Mackenzie, Jared; Tezera, Liku; Krause, Robert; Truebody, Barry; Garay-Baquero, Diana; Vallejo, Andres; Govender, Katya; Adamson, John; Fisher, Hayden; Essex, Jonathan W.; Mansour, Salah; Elkington, Paul; Steyn, Adrie J. C.; Leslie, Alasdair
- 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. Mycobacterium tuberculosis senses IFN-γ via the membrane protein MmpL10, which results in stimulation of bacterial respiration and virulence gene expression, worsens infection and paradoxically prevents the formation of isoniazid tolerant persisters.
- Subjects
MYCOBACTERIUM tuberculosis; MEMBRANE proteins; MICROBIAL respiration; OXYGEN consumption; MASS spectrometry
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-04265-0