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Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN\u2013mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.<\/jats:p>","DOI":"10.1084\/jem.20200887","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T02:22:13Z","timestamp":1600309333000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":118,"title":["Type I interferon signaling mediates\n                    <i>Mycobacterium tuberculosis<\/i>\n                    \u2013induced macrophage death"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-8473","authenticated-orcid":true,"given":"Li","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9965-8771","authenticated-orcid":true,"given":"Xiuju","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8664-598X","authenticated-orcid":true,"given":"Daniel","family":"Pfau","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5155-9766","authenticated-orcid":true,"given":"Yan","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7744-8896","authenticated-orcid":true,"given":"Carl F.","family":"Nathan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2020,10,30]]},"reference":[{"key":"2023072622503297100_bib1","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1084\/jem.20181776","article-title":"A major role for ferroptosis in Mycobacterium tuberculosis-induced cell death and tissue necrosis","volume":"216","author":"Amaral","year":"2019","journal-title":"J. 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