SSR42 is a novel regulator of cytolytic activity in Staphylococcus aureus
ABSTRACT SSR42 is the longest noncoding RNA in the Staphylococcus aureus cell and the second-most abundant transcript in the stationary-phase transcriptome, second only to RNAIII. It is highly conserved across strains and exhibits pronounced stability in stationary phase; however, the mechanism behi...
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American Society for Microbiology
2025-06-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00772-25 |
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| author | Mary-Elizabeth Jobson Brooke R. Tomlinson Emilee M. Mustor Emily A. Felton Andy Weiss Clayton C. Caswell Lindsey N. Shaw |
| author_facet | Mary-Elizabeth Jobson Brooke R. Tomlinson Emilee M. Mustor Emily A. Felton Andy Weiss Clayton C. Caswell Lindsey N. Shaw |
| author_sort | Mary-Elizabeth Jobson |
| collection | DOAJ |
| description | ABSTRACT SSR42 is the longest noncoding RNA in the Staphylococcus aureus cell and the second-most abundant transcript in the stationary-phase transcriptome, second only to RNAIII. It is highly conserved across strains and exhibits pronounced stability in stationary phase; however, the mechanism behind its regulatory role has yet to be fully elucidated. Herein, we used transcriptomic and proteomic approaches to probe the role of SSR42, revealing that it is a powerful, novel activator of the primary leukocidin LukAB. SSR42 is required for cytotoxicity toward, and escape from within, human neutrophils, and also mediates survival within human blood. We show that SSR42 wields this role via derepression by the peroxide repressor PerR in response to the presence of human neutrophils and governs lukAB induction in this niche. Importantly, this regulation is driven by direct RNA-RNA interaction, as we show binding of the 5′ untranslated region (UTR) of the lukAB transcript with the 3′ end of SSR42, which ultimately modulates transcript stability as well as translational activity. Finally, we demonstrate that this behavior is absolutely required for full virulence of S. aureus in murine models of both pneumonia and sepsis. Collectively, we present SSR42 as a pleiotropic regulatory RNA that acts as a nexus between environmental sensing and the regulation of pathogenesis, responding to environmental stimuli and host immune factors to bolster cytotoxic behavior and facilitate infection in S. aureus.IMPORTANCEStaphylococcus aureus is a master pathogen due to its formidable collection of virulence factors. These are tightly controlled by a diverse group of regulators that titrate their abundance to adapt to unique infectious niches. The role of regulatory RNAs in stress adaptation and pathogenesis is becoming increasingly more relevant in S. aureus. In this study, we provide the most comprehensive global analysis to date of just such a factor, SSR42. Specifically, we uncover that SSR42 is required for mediating cytotoxicity—one of the pillars of infection—in response to phagocytosis by human neutrophils. We find that SSR42 is induced by components of the host immune system and facilitates downstream activation of cytotoxic factors via RNA-RNA interactions. This illustrates that SSR42 forms a pivotal link between sensing the external environment and mediating resistance to oxidative stress while promoting virulence, solidifying it as a major global regulator in S. aureus. |
| format | Article |
| id | doaj-art-4e5f950a998543879d28e5cfa8600b0d |
| institution | OA Journals |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | American Society for Microbiology |
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| spelling | doaj-art-4e5f950a998543879d28e5cfa8600b0d2025-08-20T02:33:00ZengAmerican Society for MicrobiologymBio2150-75112025-06-0116610.1128/mbio.00772-25SSR42 is a novel regulator of cytolytic activity in Staphylococcus aureusMary-Elizabeth Jobson0Brooke R. Tomlinson1Emilee M. Mustor2Emily A. Felton3Andy Weiss4Clayton C. Caswell5Lindsey N. Shaw6Department of Molecular Biosciences, University of South Florida, Tampa, Florida, USADepartment of Molecular Biosciences, University of South Florida, Tampa, Florida, USADepartment of Molecular Biosciences, University of South Florida, Tampa, Florida, USADepartment of Molecular Biosciences, University of South Florida, Tampa, Florida, USADepartment of Molecular Biosciences, University of South Florida, Tampa, Florida, USADepartment of Biomedical Sciences and Pathobiology, Center for One Health Research, VA-MD College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia, USADepartment of Molecular Biosciences, University of South Florida, Tampa, Florida, USAABSTRACT SSR42 is the longest noncoding RNA in the Staphylococcus aureus cell and the second-most abundant transcript in the stationary-phase transcriptome, second only to RNAIII. It is highly conserved across strains and exhibits pronounced stability in stationary phase; however, the mechanism behind its regulatory role has yet to be fully elucidated. Herein, we used transcriptomic and proteomic approaches to probe the role of SSR42, revealing that it is a powerful, novel activator of the primary leukocidin LukAB. SSR42 is required for cytotoxicity toward, and escape from within, human neutrophils, and also mediates survival within human blood. We show that SSR42 wields this role via derepression by the peroxide repressor PerR in response to the presence of human neutrophils and governs lukAB induction in this niche. Importantly, this regulation is driven by direct RNA-RNA interaction, as we show binding of the 5′ untranslated region (UTR) of the lukAB transcript with the 3′ end of SSR42, which ultimately modulates transcript stability as well as translational activity. Finally, we demonstrate that this behavior is absolutely required for full virulence of S. aureus in murine models of both pneumonia and sepsis. Collectively, we present SSR42 as a pleiotropic regulatory RNA that acts as a nexus between environmental sensing and the regulation of pathogenesis, responding to environmental stimuli and host immune factors to bolster cytotoxic behavior and facilitate infection in S. aureus.IMPORTANCEStaphylococcus aureus is a master pathogen due to its formidable collection of virulence factors. These are tightly controlled by a diverse group of regulators that titrate their abundance to adapt to unique infectious niches. The role of regulatory RNAs in stress adaptation and pathogenesis is becoming increasingly more relevant in S. aureus. In this study, we provide the most comprehensive global analysis to date of just such a factor, SSR42. Specifically, we uncover that SSR42 is required for mediating cytotoxicity—one of the pillars of infection—in response to phagocytosis by human neutrophils. We find that SSR42 is induced by components of the host immune system and facilitates downstream activation of cytotoxic factors via RNA-RNA interactions. This illustrates that SSR42 forms a pivotal link between sensing the external environment and mediating resistance to oxidative stress while promoting virulence, solidifying it as a major global regulator in S. aureus.https://journals.asm.org/doi/10.1128/mbio.00772-25Staphylococcus aureusvirulence regulationpathogenesistoxinsSSR42 |
| spellingShingle | Mary-Elizabeth Jobson Brooke R. Tomlinson Emilee M. Mustor Emily A. Felton Andy Weiss Clayton C. Caswell Lindsey N. Shaw SSR42 is a novel regulator of cytolytic activity in Staphylococcus aureus mBio Staphylococcus aureus virulence regulation pathogenesis toxins SSR42 |
| title | SSR42 is a novel regulator of cytolytic activity in Staphylococcus aureus |
| title_full | SSR42 is a novel regulator of cytolytic activity in Staphylococcus aureus |
| title_fullStr | SSR42 is a novel regulator of cytolytic activity in Staphylococcus aureus |
| title_full_unstemmed | SSR42 is a novel regulator of cytolytic activity in Staphylococcus aureus |
| title_short | SSR42 is a novel regulator of cytolytic activity in Staphylococcus aureus |
| title_sort | ssr42 is a novel regulator of cytolytic activity in staphylococcus aureus |
| topic | Staphylococcus aureus virulence regulation pathogenesis toxins SSR42 |
| url | https://journals.asm.org/doi/10.1128/mbio.00772-25 |
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