The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureus
ABSTRACT Staphylococcus aureus is among the leading causes of hospital-acquired infections. Critical to S. aureus biology and pathogenesis are the cell wall-anchored glycopolymers wall teichoic acids (WTA). Approximately one-third of S. aureus isolates decorates WTA with a mixture of α1,4- and β1,4-...
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American Society for Microbiology
2025-01-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02668-24 |
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| author | Marieke M. Kuijk Emma Tusveld Esther Lehmann Rob van Dalen Iñigo Lasa Hanne Ingmer Yvonne Pannekoek Nina M. van Sorge |
| author_facet | Marieke M. Kuijk Emma Tusveld Esther Lehmann Rob van Dalen Iñigo Lasa Hanne Ingmer Yvonne Pannekoek Nina M. van Sorge |
| author_sort | Marieke M. Kuijk |
| collection | DOAJ |
| description | ABSTRACT Staphylococcus aureus is among the leading causes of hospital-acquired infections. Critical to S. aureus biology and pathogenesis are the cell wall-anchored glycopolymers wall teichoic acids (WTA). Approximately one-third of S. aureus isolates decorates WTA with a mixture of α1,4- and β1,4-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 α1,4- and β1,4-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 S. aureus mutants (Nebraska Transposon Mutant Library) by immunoblotting for differential expression of WTA-linked α1,4- or β1,4-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 β1,4-GlcNAc decoration. ArlRS repressed tarM expression through the transcriptional regulator MgrA. In bacteria lacking arlRS, the increased expression of tarM correlated with the absence of WTA β1,4-GlcNAc, likely by outcompeting TarS enzymatic activity. ArlRS was responsive to Mg2+, but not Na+, revealing its role in the previously reported salt-induced WTA glycoswitch from α1,4-GlcNAc to β1,4-GlcNAc. Importantly, ArlRS-mediated regulation of WTA glycosylation affected S. aureus interaction with the innate receptor langerin and lysis by β1,4-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 S. aureus WTA glycosylation patterns during infection.IMPORTANCEStaphylococcus aureus is a common colonizer but can also cause severe infections in humans. The development of antibiotic resistance complicates the treatment of S. aureus 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 S. aureus 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 Mg2+ concentration. These findings may support the design of new treatment strategies that target WTA glycosylation patterns of S. aureus during infection. |
| format | Article |
| id | doaj-art-9ad5ce01bac34fdc926c6b99c57f4dac |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Society for Microbiology |
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| spelling | doaj-art-9ad5ce01bac34fdc926c6b99c57f4dac2025-01-08T14:00:38ZengAmerican Society for MicrobiologymBio2150-75112025-01-0116110.1128/mbio.02668-24The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureusMarieke M. Kuijk0Emma Tusveld1Esther Lehmann2Rob van Dalen3Iñigo Lasa4Hanne Ingmer5Yvonne Pannekoek6Nina M. van Sorge7Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the NetherlandsLaboratory of Microbial Pathogenesis, Navarrabiomed, Universidad Pública de Navarra, Complejo Hospitalario de Navarra, IdiSNA, Pamplona, Navarra, SpainDepartment of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the NetherlandsABSTRACT Staphylococcus aureus is among the leading causes of hospital-acquired infections. Critical to S. aureus biology and pathogenesis are the cell wall-anchored glycopolymers wall teichoic acids (WTA). Approximately one-third of S. aureus isolates decorates WTA with a mixture of α1,4- and β1,4-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 α1,4- and β1,4-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 S. aureus mutants (Nebraska Transposon Mutant Library) by immunoblotting for differential expression of WTA-linked α1,4- or β1,4-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 β1,4-GlcNAc decoration. ArlRS repressed tarM expression through the transcriptional regulator MgrA. In bacteria lacking arlRS, the increased expression of tarM correlated with the absence of WTA β1,4-GlcNAc, likely by outcompeting TarS enzymatic activity. ArlRS was responsive to Mg2+, but not Na+, revealing its role in the previously reported salt-induced WTA glycoswitch from α1,4-GlcNAc to β1,4-GlcNAc. Importantly, ArlRS-mediated regulation of WTA glycosylation affected S. aureus interaction with the innate receptor langerin and lysis by β1,4-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 S. aureus WTA glycosylation patterns during infection.IMPORTANCEStaphylococcus aureus is a common colonizer but can also cause severe infections in humans. The development of antibiotic resistance complicates the treatment of S. aureus 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 S. aureus 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 Mg2+ concentration. These findings may support the design of new treatment strategies that target WTA glycosylation patterns of S. aureus during infection.https://journals.asm.org/doi/10.1128/mbio.02668-24Staphylococcus aureuswall teichoic acidglycosylationhost-pathogen interactionsvirulence regulationtwo-component regulatory systems |
| spellingShingle | Marieke M. Kuijk Emma Tusveld Esther Lehmann Rob van Dalen Iñigo Lasa Hanne Ingmer Yvonne Pannekoek Nina M. van Sorge The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureus mBio Staphylococcus aureus wall teichoic acid glycosylation host-pathogen interactions virulence regulation two-component regulatory systems |
| title | The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureus |
| title_full | The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureus |
| title_fullStr | The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureus |
| title_full_unstemmed | The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureus |
| title_short | The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureus |
| title_sort | two component system arlrs is essential for wall teichoic acid glycoswitching in staphylococcus aureus |
| topic | Staphylococcus aureus wall teichoic acid glycosylation host-pathogen interactions virulence regulation two-component regulatory systems |
| url | https://journals.asm.org/doi/10.1128/mbio.02668-24 |
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