鼠伤寒沙门氏菌小蛋白YshB介导PhoP-PhoQ双组分系统调控毒力因子的分子机制研究

我国70-80%的食源性疾病爆发是由鼠伤寒沙门氏菌引起的，深入研究其致病机制具有重要意义。鼠伤寒沙门氏菌感染有两个基本步骤：入侵细胞和胞内存活复制，感染所需的许多基因都位于染色体基因簇（致病岛，SPIs）中。SPI-1主要负责入侵细胞，SPI-2是其在胞内存活复制所必需，精确调节基因表达对整个感染过程的毒力至关重要。申请人前期研究表明，小蛋白YshB介导鼠伤寒沙门氏菌从入侵细胞到胞内存活的过渡转换，是其毒力所必需，但具体调控机制尚不清楚。我们提出了科学假说：YshB通过介导PhoP-PhoQ系统来调节毒力基因（已初步证实）。课题拟研究YshB在PhoP-PhoQ系统调控网络中的作用，确定与YshB直接相互作用的蛋白底物，并用小鼠感染模型等考察底物蛋白的生物学意义。本课题探索长期被忽视的小蛋白类分子对鼠伤寒沙门氏菌致病性的重要意义，并为开发防治沙门菌病策略提供新的潜在药物靶标和生化研

About 70-80% of foodborne disease outbreaks in China are caused by Salmonella enterica serovar Typhimurium (S. Typhimurium), so it is of great significance to study its pathogenic mechanism in depth. S. Typhimurium infection requires two essential steps: invasion of intestinal cells and intracellular survival/replication. Many of the bacterial genes required for the invasion and replication reside in a cluster of genes on the chromosome (Salmonella pathogenicity islands, SPIs). SPI-1 is mainly responsible for the invasion of intestinal host cells, and SPI-2 is required for the survival and replication of S. Typhimurium inside the host cells. Previous studies have indicated that precise regulation of gene expression is essential for S. Typhimurium virulence throughout the infection process. We have shown that the small protein YshB mediates the transition from S. Typhimurium invasion to intracellular survival, and this transition is required for S. Typhimurium virulence. How YshB function is not clear. Our preliminary work has shown that YshB may function by influencing the PhoP-PhoQ two-component system to regulate S. Typhimurium virulence genes during infection. We hypothesize that YshB interacts with the PhoP-PhoQ two-component regulatory system either directly or indirectly to regulate virulence genes. We plan to 1) characterize how YshB influences the PhoP-PhoQ two-component system and the downstream virulence products; 2) identify S. Typhimurium components that directly interact with YshB and examine their roles in S. Typhimurium virulence using a mouse infection model. This study explores the significance of small protein molecules that have long been neglected for the pathogenicity of S. Typhimurium, and provides new potential drug targets and biochemical research platforms for the development of strategies to prevent and treat Salmonellosis.