{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:14:18Z","timestamp":1788275658376,"version":"build-2803163510"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Tuberculosis vaccines aim to elicit protective immunity, with IFN\u03b3-producing CD4\u207a T cells considered central mediators of host defense. In murine models, IFN\u03b3 activates macrophages to induce inducible nitric oxide synthase (iNOS), resulting in nitric oxide\u2013dependent control of Mycobacterium tuberculosis (Mtb).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To define the relevance of IFN\u03b3-induced iNOS activity in humans and other natural host of virulent mycobacterial species.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically compared IFN\u03b3-induced effector responses in Mtb-infected myeloid cells across species. Using bulk RNA sequencing, functional infection assays, and nitric oxide measurements, we assessed IFN\u03b3 responsiveness in human and mouse macrophages. These analyses were extended to monocytes from seven mammalian species and complemented by reanalysis of publicly available single-cell RNA-sequencing datasets and spatial proteomic imaging of tuberculous granulomas.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Single-cell transcriptomic reanalysis revealed minimal NOS2 expression in myeloid cells from human and non-human primate granulomas. In vitro, IFN\u03b3 pretreatment failed to induce NOS2 transcription, iNOS activity, or Mtb growth restriction in human macrophages, in stark contrast to murine cells. Across species, iNOS activity was largely restricted to mice, with limited induction in cattle monocytes. Instead, human respiratory epithelial cells consistently expressed NOS2, and multiplexed ion beam imaging localized iNOS protein to epithelial compartments adjacent to granulomatous lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>IFN\u03b3 signaling is uncoupled from iNOS induction in primate myeloid cells and epithelial compartments represent dominant sources of iNOS in human tuberculosis. These findings, challenge murine macrophage\u2013centric paradigms and IFN\u03b3-based correlates used in tuberculosis vaccine development and central to pathophysiology of tuberculosis and other pneumonias.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ajrcmb\/aanag166","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:51:43Z","timestamp":1786535503000},"source":"Crossref","is-referenced-by-count":0,"title":["Species-specific iNOS expression distinguishes epithelial and myeloid IFN\u03b3 responses in tuberculosis"],"prefix":"10.1093","author":[{"given":"Fabian","family":"Stei","sequence":"first","affiliation":[{"name":"Greifswald - Isle of Riems Institute of Immunology, Friedrich-Loeffler-Institut, ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin F","family":"McCaffrey","sequence":"additional","affiliation":[{"name":"National Institute of Allergy and Infectious Diseases, National Institutes of Health Spatial Immunology Unit, T-Lymphocyte Biology Section, Laboratory of Parasitic Diseases, , Bethesda, MD,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Zessin","sequence":"additional","affiliation":[{"name":"Greifswald - Isle of Riems Institute of Immunology, Friedrich-Loeffler-Institut, ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Pioch","sequence":"additional","affiliation":[{"name":"Greifswald - Isle of Riems Institute of Immunology, Friedrich-Loeffler-Institut, ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Simm","sequence":"additional","affiliation":[{"name":"University of Applied Sciences Coburg Institute of Bioanalytics, ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Stubbe","sequence":"additional","affiliation":[{"name":"University Hospital Greifswald Internal Medicine B, Pneumology, , Greifswald,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Ewert","sequence":"additional","affiliation":[{"name":"University Hospital Greifswald Internal Medicine B, Pneumology, , Greifswald,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Verreck","sequence":"additional","affiliation":[{"name":"Biomedical Primate Research Centre , Rijswijk, The","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca E","family":"Schneider","sequence":"additional","affiliation":[{"name":"Priority Area Infections , Research Center Borstel-Leibniz Lung Center,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca","family":"Dorhoi","sequence":"additional","affiliation":[{"name":"Greifswald - Isle of Riems Institute of Immunology, Friedrich-Loeffler-Institut, ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan D","family":"Bryson","sequence":"additional","affiliation":[{"name":"Ragon Institute of MGH , Harvard, and MIT, Cambridge,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Corleis","sequence":"additional","affiliation":[{"name":"Greifswald - Isle of Riems Institute of Immunology, Friedrich-Loeffler-Institut, ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,1]]},"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/advance-article-pdf\/doi\/10.1093\/ajrcmb\/aanag166\/70894297\/aanag166.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/advance-article-pdf\/doi\/10.1093\/ajrcmb\/aanag166\/70894297\/aanag166.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T14:43:04Z","timestamp":1788273784000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/advance-article\/doi\/10.1093\/ajrcmb\/aanag166\/8778543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/ajrcmb\/aanag166","relation":{},"ISSN":["1535-4989"],"issn-type":[{"value":"1535-4989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"article-number":"aanag166"}}