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To sense and respond to variations in its environment, GBS possesses multiple two-component regulatory systems (TCSs), such as LytSR. Here, we aimed to investigate the role of LytSR in GBS pathogenicity. We generated an isogenic\n                      <jats:italic>lytS<\/jats:italic>\n                      knockout mutant in a clinical GBS isolate and used a combination of phenotypic\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays and\n                      <jats:italic>in vivo<\/jats:italic>\n                      murine models to investigate the contribution of\n                      <jats:italic>lytS<\/jats:italic>\n                      to the colonization and invasive properties of GBS. Deletion of the\n                      <jats:italic>lytS<\/jats:italic>\n                      gene in the GBS chromosome resulted in significantly higher survival rates in mice during sepsis, accompanied by reduced bacterial loads in blood, lung, spleen, kidney, and brain tissues compared to infection with the wild-type strain. In a mouse model of GBS vaginal colonization, we also observed that the\n                      <jats:italic>lytS<\/jats:italic>\n                      knockout mutant was cleared more readily from the vaginal tract compared to its wild-type counterpart. Interestingly, lower levels of proinflammatory cytokines were found in the serum of mice infected with the\n                      <jats:italic>lytS<\/jats:italic>\n                      mutant. Our results demonstrate that the LytSR TCS plays a key role in GBS tissue invasion and pathogenesis, and persistence of mucosal colonization.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic>Streptococcus agalactiae (<\/jats:italic>\n                        group B\n                        <jats:italic>Streptococcus,<\/jats:italic>\n                        or GBS) is a common commensal of the female urogenital tract and one of WHO\u2019s priority pathogens. The bacterium has evolved mechanisms to adapt and survive in its host, many of which are regulated via two-component signal transduction systems (TCSs); however, the exact contributions of TCSs toward GBS pathogenicity remain largely obscure. We have constructed a TCS\n                        <jats:italic>lytS-<\/jats:italic>\n                        deficient mutant in a CC-17 hypervirulent GBS clinical isolate. Using murine models, we showed that LytSR regulatory system is essential for vaginal colonization via promoting biofilm production. We also observed that\n                        <jats:italic>lytS<\/jats:italic>\n                        deficiency led to significantly attenuated virulence properties and lower levels of proinflammatory cytokines in blood. Our findings are of significant importance in that they unveil a previously unreported role for LytSR in GBS and pave the way toward a better understanding of its ability to transition from an innocuous commensal to a deadly pathogen.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01970-24","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T09:00:18Z","timestamp":1728896418000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["The\n                    <i>Streptococcus agalactiae<\/i>\n                    LytSR two-component regulatory system promotes vaginal colonization and virulence\n                    <i>in 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