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Several cytokines are known to increase virulence of bacterial pathogens, leading us to investigate whether Interferon-\u03b3 (IFN-\u03b3), a central regulator of the immune defense against\n                    <jats:italic>Mtb<\/jats:italic>\n                    , has a direct effect on the bacteria. We found that recombinant and T-cell derived IFN-\u03b3 rapidly induced a dose-dependent increase in the oxygen consumption rate (OCR) of\n                    <jats:italic>Mtb<\/jats:italic>\n                    , consistent with increased bacterial respiration. This was not observed in attenuated Bacillus Calmette\u2013Gu\u00e9rin (BCG), and did not occur for other cytokines tested, including TNF-\u03b1. IFN-\u03b3 binds to the cell surface of intact\n                    <jats:italic>Mtb<\/jats:italic>\n                    , but not BCG. Mass spectrometry identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner of IFN-\u03b3, supported by molecular modelling studies. IFN-\u03b3 binding and the OCR response was absent in\n                    <jats:italic>Mtb \u0394mmpl10<\/jats:italic>\n                    strain and restored by complementation with wildtype\n                    <jats:italic>mmpl10<\/jats:italic>\n                    . RNA-sequencing and RT-PCR of\n                    <jats:italic>Mtb<\/jats:italic>\n                    exposed to IFN-\u03b3 revealed a distinct transcriptional profile, including genes involved in virulence. In a 3D granuloma model, IFN-\u03b3 promoted\n                    <jats:italic>Mtb<\/jats:italic>\n                    growth, which was lost in the\n                    <jats:italic>Mtb \u0394mmpl10<\/jats:italic>\n                    strain and restored by complementation, supporting the involvement of MmpL10 in the response to IFN-\u03b3. Finally, IFN-\u03b3 addition resulted in sterilization of\n                    <jats:italic>Mtb<\/jats:italic>\n                    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\n                    <jats:italic>Mtb<\/jats:italic>\n                    to respond to host immune activation that may be important in the immunopathogenesis of TB and have use in novel eradication strategies.\n                  <\/jats:p>","DOI":"10.1038\/s42003-022-04265-0","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T08:05:50Z","timestamp":1669881950000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Mycobacterium tuberculosis senses host Interferon-\u03b3 via the membrane protein MmpL10"],"prefix":"10.1038","volume":"5","author":[{"given":"Mohamed","family":"Ahmed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3089-0900","authenticated-orcid":false,"given":"Jared","family":"Mackenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liku","family":"Tezera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Krause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7066-3916","authenticated-orcid":false,"given":"Barry","family":"Truebody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Garay-Baquero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4688-0598","authenticated-orcid":false,"given":"Andres","family":"Vallejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katya","family":"Govender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Adamson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0093-0921","authenticated-orcid":false,"given":"Hayden","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2639-2746","authenticated-orcid":false,"given":"Jonathan W.","family":"Essex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5982-734X","authenticated-orcid":false,"given":"Salah","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Elkington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrie J. 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