{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T23:51:54Z","timestamp":1770681114217,"version":"3.49.0"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["HL105427, AI111914-02, AI134236-02, AI123780"],"award-info":[{"award-number":["HL105427, AI111914-02, AI134236-02, AI123780"]}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["T32 HL007317-42"],"award-info":[{"award-number":["T32 HL007317-42"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["T32 HL007317-37"],"award-info":[{"award-number":["T32 HL007317-37"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2023,10,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Tuberculosis (TB) is one of the leading causes of death due to an infectious disease. The rise of multi-drug resistance (MDR) in\n            <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n            (\n            <jats:italic>Mtb<\/jats:italic>\n            ), the causative agent of TB, presents a significant obstacle to TB control. While human studies report dysregulated immune responses during MDR TB, a clear understanding of the host-pathogen interactions of MDR\n            <jats:italic>Mtb<\/jats:italic>\n            is lacking. Here, we studied the immune responses induced by\n            <jats:italic>Mtb<\/jats:italic>\n            strains carrying two of the most common rifampicin drug-resistance (RDR)-conferring single-nucleotide polymorphisms (SNPs) in the RNA polymerase gene of\n            <jats:italic>Mtb<\/jats:italic>\n            , which accounts for nearly 90% of drug-resistance mutations found clinically in\n            <jats:italic>Mtb<\/jats:italic>\n            . During\n            <jats:italic>Mtb<\/jats:italic>\n            infection of primary human macrophages, we found that pro-inflammatory cytokine production was reduced upon infection with\n            <jats:italic>Mtb<\/jats:italic>\n            carrying the H445Y SNP but not the S450L SNP. Using a mouse model, we also characterized the host immune response\n            <jats:italic>in vivo<\/jats:italic>\n            following infection. Despite similar establishment of\n            <jats:italic>Mtb<\/jats:italic>\n            infection in the lung and dissemination to the peripheral organs, we show that infection with the RDR\n            <jats:italic>Mtb rpoB<\/jats:italic>\n            -H445Y strain, but not with the\n            <jats:italic>rpoB<\/jats:italic>\n            -S450L strain, resulted in a suppressed lung myeloid and lymphoid immune responses through type I IFN-dependent pathways, relative to\n            <jats:italic>wt Mtb<\/jats:italic>\n            . This suppressed host immunity had functional consequences in limiting control of RDR\n            <jats:italic>Mtb<\/jats:italic>\n            strains harboring\n            <jats:italic>rpoB<\/jats:italic>\n            -H445Y and led to worse pathology during chronic TB disease. Collectively, our results suggest that disease pathogenesis may be associated with specific RDR mutations in\n            <jats:italic>Mtb<\/jats:italic>\n            , which may differentially regulate immune responses.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              This study highlights the impact of specific rifampicin-resistance-conferring mutations on the host immune response to\n              <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n              (\n              <jats:italic>Mtb<\/jats:italic>\n              ), the causative agent of tuberculosis (TB). Clinical reports have previously suggested that multi-drug-resistant) TB patients exhibit altered peripheral immune responses as compared with their drug-sensitive TB counterparts. The murine model of infection with\n              <jats:italic>Mtb<\/jats:italic>\n              strains carrying drug-resistance-conferring mutations recapitulated these findings and allowed us to mechanistically interrogate the pathways responsible for driving the divergent immune responses. Our findings underscore the need for greater investigation into bacterial heterogeneity to better appreciate the diversity in host-pathogen interactions during TB disease.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.00946-23","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T13:17:10Z","timestamp":1694179030000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["<i>Mycobacterium tuberculosis<\/i>\n            carrying the rifampicin drug-resistance-conferring\n            <i>rpoB<\/i>\n            mutation H445Y is associated with suppressed immunity through type I interferons"],"prefix":"10.1128","volume":"14","author":[{"given":"Suhas","family":"Bobba","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole C.","family":"Howard","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shibali","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mushtaq","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USA"},{"name":"Department of Microbiology, University of Chicago , Chicago, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linrui","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Columbia University Mailman School of Public Health , New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyamala","family":"Thirunavukkarasu","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle H.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barun","family":"Mathema","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Columbia University Mailman School of Public Health , New York, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maziar","family":"Divangahi","sequence":"additional","affiliation":[{"name":"Meakins-Christie Laboratories, Department of Medicine, McGill University , Montreal, Quebec, Canada"},{"name":"Department of Microbiology and Immunology, McGill International TB Centre , Montreal, Quebec, Canada"},{"name":"Department of Pathology, McGill University Health Centre , Montreal, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9545-4982","authenticated-orcid":true,"given":"Shabaana A.","family":"Khader","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine , St. Louis, Missouri, USA"},{"name":"Department of Microbiology, University of Chicago , Chicago, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_6_2_2","unstructured":"Published online 2022. 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