Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Virulence. 2023 Dec;14(1):2228657. doi: 10.1080/21505594.2023.2228657.
The virulence factors of are tightly controlled by two-component systems (TCSs) and small RNA (sRNA). TCSs have been well studied over the past several decades, but our understanding of sRNA functions lags far behind that of TCS functions. Here, we studied the biological role of sRNA from 506 RNA-seq datasets using independent component analysis (ICA). We found that a previously neglected sRNA, Sau-41, functions in the Agr system. Sau-41 is located within the PSMα operon and controlled by the Agr system. It was predicted to share 22-base complementarity with RNAIII, a major regulator of virulence. The EMSA results demonstrated that Sau-41 directly binds to RNAIII. Furthermore, our results found that Sau-41 is capable of repressing haemolysin activity by downregulating α-haemolysin and δ-toxin. The repression of α-haemolysin was attributed to the competition between the 5' UTR of and Sau-41 for binding RNAIII. We observed that Sau-41 mitigated virulence in an orthopaedic implant infection mouse model and alleviated osteolysis. Together, our results indicate that Sau-41 is a virulence-regulating RNA and suggest that Sau-41 might be involved in a negative feedback mechanism to control the Agr system. This work is a demonstration of using ICA in sRNA identification by mining high-throughput data and could be extended to other organisms as well.
是一种具有严格调控机制的病原菌，其毒力因子受到双组份系统（TCS）和小 RNA（sRNA）的调控。在过去的几十年中，TCS 已经得到了广泛的研究，但我们对 sRNA 功能的理解远远落后于对 TCS 功能的理解。在这里，我们使用独立成分分析（ICA）方法，从 506 个 RNA-seq 数据集研究了 sRNA 的生物学作用。我们发现，一个以前被忽视的 sRNA Sau-41 在 Agr 系统中发挥作用。Sau-41 位于 PSMα 操纵子内，并受 Agr 系统调控。预测它与 RNAIII 具有 22 个碱基的互补性，而 RNAIII 是调控毒力的主要调节因子。EMSA 结果表明 Sau-41 可直接与 RNAIII 结合。此外，我们的结果表明 Sau-41 通过下调α-溶血素和δ-毒素来抑制溶血素活性。抑制α-溶血素归因于 RNAIII 与 Sau-41 的 5'UTR 之间的竞争。我们观察到 Sau-41 在骨科植入物感染小鼠模型中降低了毒力并减轻了骨溶解。总之，我们的结果表明 Sau-41 是一种调节毒力的 RNA，并提示 Sau-41 可能参与了 Agr 系统的负反馈机制。这项工作展示了使用 ICA 通过挖掘高通量数据鉴定 sRNA 的方法，并且可以扩展到其他生物体。
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