Investigating the small peptide Tsr37, its role in virulence, and activation of the SaeRS two component system in Staphylococcus aureus

研究金黄色葡萄球菌中的小肽 Tsr37、其毒力作用以及 SaeRS 二组分系统的激活

• 批准号: 10372077
• 负责人: Ronan Carroll
• 金额: $ 18.88万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372077
• 关键词: Affinity; Amino Acids; Architecture; Bacterial Adhesins; Bacterial Infections; Binding; Biological; Cell Wall; Cells; Coenzyme A; Complex; Consensus; Dangerousness; Data; Development; Environment; Equilibrium; Future; Gene Expression; Genes; Genetic Transcription; Human; Human body; Immune Evasion; Infection; Integral Membrane Protein; Laboratories; Lead; Mediating; Modeling; Mus; Nature; Organ; Pathogenesis; Pathogenicity; Peptides; Phosphoric Monoester Hydrolases; Phosphotransferases; Point Mutation; Production; Proteins; RNA; Regulation; Role; Sepsis; Signal Transduction; Site; Staphylococcus aureus; Staphylococcus aureus infection; Superantigens; System; Systemic infection; Testing; Toxin; Up-Regulation; Variant; Virulence; Virulence Factors; Work; alpha-Defensins; base; design; exoenzyme; gene product; genetic approach; human neutrophil peptide 1; in vivo; inhibitor; mutant; novel; novel therapeutics; overexpression; pathogenic bacteria; promoter; protein-histidine kinase; response; sensor; virtual

PROJECT SUMMARY/ABSTRACT Staphylococcus aureus is both a commensal of humans and a highly dangerous bacterial pathogen. S. aureus pathogenesis is mediated by a large repertoire of secreted and cell wall-associated virulence factors. To mount successful infections the bacteria must regulate expression of the genes encoding these virulence factors in a temporal and spatial manner. Two component signal transduction systems (TCS) are one type of regulatory circuit that bacterial cells use to sense their environment and modify gene expression accordingly. The Sae TCS is a global regulator of secreted protein production in S. aureus and a variety of well-studied virulence factors are known to be directly controlled by the Sae system. Activity of the Sae system is dependent on the balance between the kinase and phosphatase activities of the sensor protein SaeS. Human neutrophil peptide 1 (HNP-1) is known to activate SaeS kinase activity, while the Sae auxiliary proteins SaePQ induce phosphatase activity. Recent work in our laboratory has identified a potent, novel activator of the Sae system. Overexpression of the tsr37 gene in S. aureus results in a dramatic increase in Sae activity and upregulation of Sae target genes. In this proposal we will investigate the nature of the tsr37 gene product, investigate how tsr37 activates the Sae system, and determine the contribution of tsr37 to virulence. In addition, we will study the in vivo expression profile of tsr37 to determine when and where it is expressed during systemic infection. We anticipate that the results from this study will demonstrate that a short protein, Tsr37, acts as a potent activator of the Sae TCS. Understanding how a small peptide interacts with, and activates, the Sae system could inform future studies to design Sae inhibitors which could be used as a novel therapeutic to treat S. aureus infection.

项目摘要/摘要 金黄色葡萄球菌既是人类的寄生虫，也是一种高度危险的细菌病原体。S.金黄色 致病性由大量分泌的和细胞壁相关的毒力因子介导。安装 成功的感染，细菌必须调节编码这些毒力因子的基因的表达， 时间和空间的方式。双组分信号转导系统（TCS）是一种调节性的信号转导系统。 细菌细胞用来感知环境并相应地改变基因表达的电路。的Sae TCS是S.金黄色葡萄球菌和各种研究充分的毒力 已知这些因素直接由Sae系统控制。Sae系统的活动取决于 传感蛋白SaeS的激酶和磷酸酶活性之间的平衡。人中性粒细胞肽 已知HNP-1激活SaeS激酶活性，而Sae辅助蛋白SaePQ诱导 磷酸酶活性我们实验室最近的工作已经确定了一种有效的，新的Sae系统激活剂。 将tsr 37基因在S.金黄色葡萄球菌导致Sae活性显著增加， Sae靶基因。在本提案中，我们将研究tsr 37基因产物的性质，研究如何 tsr 37激活Sae系统，并确定tsr 37对毒力的贡献。此外，我们将研究 TSR 37的体内表达谱，以确定其在全身感染期间何时和何处表达。 我们预计，这项研究的结果将证明，一个短蛋白，Tsr 37，作为一个有效的 Sae TCS的激活剂。了解小肽如何与Sae系统相互作用并激活Sae系统 可以为将来设计Sae抑制剂的研究提供信息，这些抑制剂可以用作治疗S. 金黄色葡萄球菌感染。

项目成果

The Small Protein ScrA Influences Staphylococcus aureus Virulence-Related Processes via the SaeRS System.

小蛋白 ScrA 通过 SaeRS 系统影响金黄色葡萄球菌毒力相关过程。

• DOI: 10.1128/spectrum.05255-22
• 发表时间: 2023-06-15
• 期刊: Microbiology spectrum
• 影响因子: 3.7

The novel protein ScrA acts through the SaeRS two-component system to regulate virulence gene expression in Staphylococcus aureus.

• DOI: 10.1111/mmi.14901
• 发表时间: 2022-05
• 期刊: MOLECULAR MICROBIOLOGY
• 影响因子: 3.6
• 作者: Wittekind, Marcus A.;Frey, Andrew;Bonsall, Abigail E.;Briaud, Paul;Keogh, Rebecca A.;Wiemels, Richard E.;Shaw, Lindsey N.;Carroll, Ronan K.
• 通讯作者: Carroll, Ronan K.