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Critical to\n                      <jats:italic>S. aureus<\/jats:italic>\n                      biology and pathogenesis are the cell wall-anchored glycopolymers wall teichoic acids (WTA). Approximately one-third of\n                      <jats:italic>S. aureus<\/jats:italic>\n                      isolates decorates WTA with a mixture of \u03b11,4- and \u03b21,4-\n                      <jats:italic>N<\/jats:italic>\n                      -acetylglucosamine (GlcNAc), which requires the dedicated glycosyltransferases TarM and TarS, respectively. Environmental conditions, such as high salt concentrations, affect the abundance and ratio of \u03b11,4- and \u03b21,4-GlcNAc WTA decorations, thereby impacting biological properties such as antibody binding and phage infection. To identify regulatory mechanisms underlying WTA glycoswitching, we screened 1,920\n                      <jats:italic>S<\/jats:italic>\n                      .\n                      <jats:italic>aureus<\/jats:italic>\n                      mutants (Nebraska Transposon Mutant Library) by immunoblotting for differential expression of WTA-linked \u03b11,4- or \u03b21,4-GlcNAc using specific monoclonal antibody Fab fragments. Three two-component systems (TCS), GraRS, ArlRS, and AgrCA, were among the 230 potential hits. Using isogenic TCS mutants, we demonstrated that ArlRS is essential for WTA \u03b21,4-GlcNAc decoration. ArlRS repressed\n                      <jats:italic>tarM<\/jats:italic>\n                      expression through the transcriptional regulator MgrA. In bacteria lacking\n                      <jats:italic>arlRS<\/jats:italic>\n                      , the increased expression of\n                      <jats:italic>tarM<\/jats:italic>\n                      correlated with the absence of WTA \u03b21,4-GlcNAc, likely by outcompeting TarS enzymatic activity. ArlRS was responsive to Mg\n                      <jats:sup>2+<\/jats:sup>\n                      , but not Na\n                      <jats:sup>+<\/jats:sup>\n                      , revealing its role in the previously reported salt-induced WTA glycoswitch from \u03b11,4-GlcNAc to \u03b21,4-GlcNAc. Importantly, ArlRS-mediated regulation of WTA glycosylation affected\n                      <jats:italic>S. aureus<\/jats:italic>\n                      interaction with the innate receptor langerin and lysis by \u03b21,4-GlcNAc-dependent phages. Since WTA represents a promising target for future immune-based treatments and vaccines, our findings provide important insight to align strategies targeting\n                      <jats:italic>S. aureus<\/jats:italic>\n                      WTA glycosylation patterns during infection.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic>Staphylococcus aureus<\/jats:italic>\n                        is a common colonizer but can also cause severe infections in humans. The development of antibiotic resistance complicates the treatment of\n                        <jats:italic>S. aureus<\/jats:italic>\n                        infections, increasing the need for antibiotic alternatives such as vaccines and therapies with bacterial viruses also known as phages. Wall teichoic acids (WTA) are abundant glycosylated structures of the\n                        <jats:italic>S. aureus<\/jats:italic>\n                        cell wall that have gained attention as a promising target for new treatments. Importantly, WTA glycosylation patterns show variation depending on environmental conditions, thereby impacting phage binding and interaction with host factors, such as antibodies and innate pattern-recognition receptors. Here, we show that the two-component system ArlRS is involved in the regulation of WTA glycosylation by responding to environmental changes in Mg\n                        <jats:sup>2+<\/jats:sup>\n                        concentration. These findings may support the design of new treatment strategies that target WTA glycosylation patterns of\n                        <jats:italic>S. aureus<\/jats:italic>\n                        during infection.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02668-24","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T10:49:32Z","timestamp":1732877372000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["The two-component system ArlRS is essential for wall teichoic acid glycoswitching in\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8763-2702","authenticated-orcid":false,"given":"Marieke M.","family":"Kuijk","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Infection 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