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Despite sharing over 99% genomic identity,\n                      <jats:italic toggle=\"yes\">MTB<\/jats:italic>\n                      strains and lineages show significant variability in transmissibility. We hypothesized that natural polymorphisms in the two-component regulatory system (TCS) PhoP-PhoR (PhoPR), a major virulence regulator, contribute to this variability.\n                    <\/jats:p>\n                    <jats:p>\n                      First, we identified zinc and cadmium as new inducers of PhoPR. Second, we expressed\n                      <jats:italic toggle=\"yes\">phoPR<\/jats:italic>\n                      variants from strains with varying transmissibility in the\n                      <jats:italic toggle=\"yes\">MTB<\/jats:italic>\n                      HN878 strain and compared the variants\u2019 capacity to induce the expression of PhoP-controlled genes (PhoPR activity) after being submitted to various chemical or cellular signals.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      , PhoPR systems from HN878 and the low-transmissibility strain\n                      <jats:italic toggle=\"yes\">M. canettii<\/jats:italic>\n                      STB-D responded similarly to acidic and zinc stresses. In contrast, PhoPR variants from strains\n                      <jats:italic toggle=\"yes\">M. canettii<\/jats:italic>\n                      STB-J and\n                      <jats:italic toggle=\"yes\">M. bovis<\/jats:italic>\n                      AN5 showed reduced responsiveness. However, the former seems constitutively activated, whereas the latter displays low activity. Interestingly, although the variant found in\n                      <jats:italic toggle=\"yes\">M. bovis<\/jats:italic>\n                      B, which was responsible for direct transmission in humans in contrast to most\n                      <jats:italic toggle=\"yes\">M. bovis<\/jats:italic>\n                      strains, did not respond to acidic or zinc stress\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , it remained inducible in macrophages. Finally, we compared the virulence of the various recombinant strains in C3HeB\/FeJ mice. We found that only the strain expressing the PhoPR variant from\n                      <jats:italic toggle=\"yes\">M. bovis<\/jats:italic>\n                      AN5 is associated with reduced virulence.\n                    <\/jats:p>\n                    <jats:p>\n                      These findings indicate that both\n                      <jats:italic toggle=\"yes\">phoPR<\/jats:italic>\n                      polymorphisms and the strain-specific genetic context modulate PhoPR activity, thereby influencing\n                      <jats:italic toggle=\"yes\">MTB<\/jats:italic>\n                      virulence and potentially its transmissibility.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Understanding genomic adaptations favoring persistence and transmission of tuberculosis bacilli is crucial for developing new strategies to combat tuberculosis. This study explores the impact of natural mutations on the response to environmental cues of the two-component regulatory system (TCS) PhoP-PhoR (PhoPR), which controls the expression of major virulence factors, and on the virulence of\n                        <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                        (\n                        <jats:italic toggle=\"yes\">MTB<\/jats:italic>\n                        ). Our findings identify new signals activating PhoPR and provide new insights into the molecular mechanisms of PhoPR. In addition, this study highlights how\n                        <jats:italic toggle=\"yes\">phoPR<\/jats:italic>\n                        polymorphisms may influence the epidemic capacity of tuberculosis bacilli.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00939-26","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T13:00:48Z","timestamp":1780059648000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["PhoPR variants from several phylogenetic lineages of tuberculosis bacilli respond differently to extracellular signals"],"prefix":"10.1128","volume":"17","author":[{"given":"Eva","family":"Meunier","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ahyrz84","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut de Pharmacologie et de Biologie Structurale (IPBS), 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