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Here, we combined high-resolution imaging, transcriptomic profiling, intracellular reporter assays, and mouse infection models to define how\n                      <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                      responds to physiologically relevant copper levels during infection. NanoSIMS analysis showed that copper reaches intracellular bacilli and accumulates in discrete phosphorus-rich foci in bacteria. Exposure to physiological copper concentrations\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      triggered a highly specific transcriptional response dominated by the copper-inducible CsoR and RicR regulons. The RicR-regulated\n                      <jats:italic toggle=\"yes\">cysK2<\/jats:italic>\n                      gene, encoding the (\n                      <jats:italic toggle=\"yes\">S<\/jats:italic>\n                      -sulfo)cysteine synthase CysK2, was one of the most strongly induced loci. In infected macrophages,\n                      <jats:italic toggle=\"yes\">cysK2<\/jats:italic>\n                      expression was modulated by extracellular copper availability, host copper transport pathways, and hypoxia.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      , the H37Rv\n                      <jats:italic toggle=\"yes\">cysK2<\/jats:italic>\n                      -deficient mutant showed reduced long-term persistence in mice and a shift toward a more oxidized redox potential. Together, these findings identify CysK2 as a copper-responsive effector linking host-derived copper sensing to redox homeostasis and contributing to long-term persistence during infection.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Successful infection by\n                        <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                        depends on its ability to detect and adapt to host-imposed changes in the phagosomal environment. Our work shows that copper contributes to this adaptation not simply by imposing toxicity, but by triggering a response that helps sustain bacterial fitness within host cells. We identify CysK2 as a key component of this response, linking copper sensing to sulfur metabolism, redox balance, and persistence during infection. These findings shift the view of copper from a purely antimicrobial factor to a host-derived environmental signal that remodels\n                        <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                        physiology, and they uncover a new mechanism by which the pathogen maintains intracellular survival.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00816-26","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:02:23Z","timestamp":1788872543000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["CysK2 couples copper sensing to redox adaptation in\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3251-036X","authenticated-orcid":false,"given":"Wendy","family":"Le Mou\u00ebllic","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ahyrz84","id-type":"ROR","asserted-by":"publisher"}],"name":"Univ Toulouse, CNRS, IPBS","place":["Toulouse, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Levillain","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ahyrz84","id-type":"ROR","asserted-by":"publisher"}],"name":"Univ Toulouse, CNRS, IPBS","place":["Toulouse, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Di","family":"Wu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjwb503","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Curie, CNRS Unit\u00e9 d'Appui et de Recherche UAR2016, Inserm Unit\u00e9 de Service US43, Universit\u00e9 Paris-Saclay, Multimodal Imaging Center","place":["Orsay, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e9rald","family":"Larrouy-Maumus","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041kmwe10","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Bacterial Resistance Biology, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Lagarrigue","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ahyrz84","id-type":"ROR","asserted-by":"publisher"}],"name":"Univ Toulouse, CNRS, IPBS","place":["Toulouse, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith","family":"Vidal","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ahyrz84","id-type":"ROR","asserted-by":"publisher"}],"name":"Univ Toulouse, CNRS, IPBS","place":["Toulouse, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoann","family":"Rombouts","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ahyrz84","id-type":"ROR","asserted-by":"publisher"}],"name":"Univ Toulouse, CNRS, IPBS","place":["Toulouse, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6430-6095","authenticated-orcid":false,"given":"Yannick","family":"Poquet","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ahyrz84","id-type":"ROR","asserted-by":"publisher"}],"name":"Univ Toulouse, CNRS, IPBS","place":["Toulouse, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0047-5885","authenticated-orcid":true,"given":"Olivier","family":"Neyrolles","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ahyrz84","id-type":"ROR","asserted-by":"publisher"}],"name":"Univ Toulouse, CNRS, IPBS","place":["Toulouse, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_6_2_2","unstructured":"World Health Organization. 2025. 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