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We discovered that transient depletion of biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent infections during which Mtb cannot be detected but that relapse in a subset of mice. The immune requirements for Mtb control during latency, and the frequency of relapse, were strikingly different depending on how latency was established. TrxB2 depletion resulted in a latent infection that required adaptive immunity for control and reactivated with high frequency, whereas latent infection after BPL depletion was independent of adaptive immunity and rarely reactivated. We identified immune signatures of T cells indicative of relapse and demonstrated that BCG vaccination failed to protect mice from TB relapse. These reproducible genetic latency models allow investigation of the host immunological determinants that control the latent state and offer opportunities to evaluate therapeutic strategies in settings that mimic aspects of latency and TB relapse in humans.<\/jats:p>","DOI":"10.1084\/jem.20210332","type":"journal-article","created":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T02:21:34Z","timestamp":1625019694000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8345-3560","authenticated-orcid":true,"given":"Hongwei","family":"Su","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5181-4616","authenticated-orcid":true,"given":"Kan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7631-2471","authenticated-orcid":true,"given":"Divya","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6903-2455","authenticated-orcid":true,"given":"Claire","family":"Healy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9601-820X","authenticated-orcid":true,"given":"Carolina","family":"Trujillo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4330-2389","authenticated-orcid":true,"given":"Yao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8702-9102","authenticated-orcid":true,"given":"Thomas R.","family":"Ioerger","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, Texas A&M University, College Station, TX 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4445-7219","authenticated-orcid":true,"given":"Dirk","family":"Schnappinger","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7951-2310","authenticated-orcid":true,"given":"Sabine","family":"Ehrt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,7,16]]},"reference":[{"key":"2023072813045172500_bib1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.tim.2006.11.008","article-title":"Vaccine strategies against latent tuberculosis infection","volume":"15","author":"Andersen","year":"2007","journal-title":"Trends Microbiol."},{"key":"2023072813045172500_bib2","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.it.2014.04.006","article-title":"Tuberculosis vaccines--rethinking the current paradigm","volume":"35","author":"Andersen","year":"2014","journal-title":"Trends Immunol."},{"key":"2023072813045172500_bib3","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nrmicro2236","article-title":"The spectrum of latent tuberculosis: rethinking the biology and intervention strategies","volume":"7","author":"Barry","year":"2009","journal-title":"Nat. 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