Jobson Mary-Elizabeth, Tomlinson Brooke R, Mustor Emilee M, Felton Emily A, Weiss Andy, Caswell Clayton C, Shaw Lindsey N
Department of Molecular Biosciences, University of South Florida, Tampa, Florida, USA.
Center for Antimicrobial Resistance, University of South Florida, Tampa, Florida, USA.
mBio. 2025 Jun 11;16(6):e0077225. doi: 10.1128/mbio.00772-25. Epub 2025 May 9.
SSR42 is the longest noncoding RNA in the 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 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 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 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 .IMPORTANCE 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 . 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 .
SSR42是细胞中最长的非编码RNA，也是稳定期转录组中第二丰富的转录本，仅次于RNAIII。它在不同菌株间高度保守，在稳定期表现出显著的稳定性；然而，其调控作用背后的机制尚未完全阐明。在此，我们运用转录组学和蛋白质组学方法探究SSR42的作用，发现它是主要杀白细胞素LukAB的一种强大的新型激活剂。SSR42对于对人类中性粒细胞的细胞毒性以及从中逃逸是必需的，并且还介导在人血液中的存活。我们表明，SSR42通过过氧化物阻遏物PerR的去阻遏作用发挥这一作用，以响应人类中性粒细胞的存在，并在该生态位中调控诱导。重要的是，这种调控是由直接的RNA-RNA相互作用驱动的，正如我们所展示的转录本的5'非翻译区（UTR）与SSR42的3'末端的结合，这最终调节了转录本稳定性以及翻译活性。最后，我们证明这种行为对于在肺炎和败血症的小鼠模型中的完全毒力是绝对必需的。总体而言，我们将SSR42呈现为一种多效性调控RNA，它作为环境感知与发病机制调控之间的枢纽，响应环境刺激和宿主免疫因子以增强细胞毒性行为并促进感染。重要性是一种主要病原体，因其拥有大量强大的毒力因子。这些因子受到多种调节因子的严格控制，这些调节因子调节它们的丰度以适应独特的感染生态位。调控RNA在应激适应和发病机制中的作用在中变得越来越重要。在这项研究中，我们提供了迄今为止对这样一个因子SSR42最全面的全局分析。具体而言，我们发现SSR42是介导细胞毒性（感染的支柱之一）以响应人类中性粒细胞吞噬作用所必需的。我们发现SSR42由宿主免疫系统的成分诱导，并通过RNA-RNA相互作用促进细胞毒性因子的下游激活。这表明SSR42在感知外部环境与介导对氧化应激的抗性同时促进毒力之间形成了关键联系，巩固了它作为中的一个主要全局调节因子的地位。
