INTRODUCTION: Bacterial small non-coding RNAs (sRNAs) play critical roles in virulence, stress adaptation, and host-pathogen interactions. Transcriptomic analyses during infection can help reveal pathogen-derived sRNAs required for pathogenesis, providing valuable insights for the development of novel therapeutic strategies. However, the low abundance of pathogen biomass within the host tissues poses a significant challenge for such analyses. METHODS: We employed two-step cell disruption to enrich Staphylococcus aureus cells from infected mouse organs and conducted RNA-seq analysis to examine staphylococcal sRNAs expressed during infection. qRT-PCR was used to confirm the gene expression. A knockout mutant of highly expressed sRNA, RsaC, was generated, and RNA-seq under in vivo as well as in vitro aerobic and anaerobic conditions were compared between the wild-type and ΔrsaC strains. Virulence of S. aureus was assessed using both mouse and silkworm survival assays. RESULTS: We identified RsaC as one of the most highly expressed sRNAs in mouse organ with consistent increment over time post-infection. Through gene disruption and complementation, we demonstrated that RsaC is an independent virulence determinant required for full pathogenicity of S. aureus in a murine infection model. Besides, rsaC influenced gene expression in response to oxygen availability and host-associated stress. Further analysis revealed that mutation of two genes downregulated in ΔrsaC in vivo, NWMNRS03420 (sodium: proton antiporter) and NWMNRS12015 (hypothetical protein), reduced S. aureus virulence in a silkworm model. CONCLUSION: These findings identify RsaC as a novel independent virulence determinant that supports S. aureus adaptation within the host.
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