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Despite strong selective pressure,\n                    <jats:italic>M.tb<\/jats:italic>\n                    shows frequent deletions at the\n                    <jats:italic>PPE71<\/jats:italic>\n                    \u2013\n                    <jats:italic>38<\/jats:italic>\n                    locus, most notably in hypervirulent L2 Beijing strains. Here, we show that loss of the\n                    <jats:italic>PPE71<\/jats:italic>\n                    \u2013\n                    <jats:italic>38<\/jats:italic>\n                    locus causes increased stress response gene expression and increased triglyceride levels. In addition, we demonstrate that reintroduction of\n                    <jats:italic>PPE71<\/jats:italic>\n                    into the L2 strain HN878 suppresses the baseline elevation of these transcripts, while overexpression of\n                    <jats:italic>PPE71<\/jats:italic>\n                    increases the localization of PE_PGRS proteins and lipoproteins to the\n                    <jats:italic>M.tb<\/jats:italic>\n                    outer mycomembrane. Mouse infection confirmed the hypervirulence of the\n                    <jats:italic>PPE71<\/jats:italic>\n                    \u2013\n                    <jats:italic>38<\/jats:italic>\n                    deletion strain and conversely showed that\n                    <jats:italic>PPE71<\/jats:italic>\n                    overexpression attenuates\n                    <jats:italic>M.tb<\/jats:italic>\n                    . Our results indicate that loss of\n                    <jats:italic>PPE71<\/jats:italic>\n                    \u2013\n                    <jats:italic>38<\/jats:italic>\n                    is sufficient to drive an adaptive transcriptional response seen in\n                    <jats:italic>M.tb<\/jats:italic>\n                    L2 strains that likely contributes to the hypervirulence of this lineage.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adw5194","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T13:59:13Z","timestamp":1751464753000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Loss of the\n                    <i>PPE71-esxX-esxY-PPE38<\/i>\n                    locus drives adaptive transcriptional responses and hypervirulence of\n                    <i>Mycobacterium tuberculosis<\/i>\n                    lineage 2"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1479-218X","authenticated-orcid":true,"given":"Benjamin","family":"Koleske","sequence":"first","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2841-7612","authenticated-orcid":true,"given":"Courtney","family":"Schill","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2201-8028","authenticated-orcid":true,"given":"Saranathan","family":"Rajagopalan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9313-8559","authenticated-orcid":true,"given":"Somnath","family":"Shee","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazmin B.","family":"Martinez-Martinez","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-6096","authenticated-orcid":true,"given":"Manish","family":"Gupta","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, 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