PagR mediates the precise regulation of Salmonella pathogenicity island 2 gene expression in response to magnesium and phosphate signals in Salmonella Typhimurium

To establish systemic infections, Salmonella enterica serovar Typhimurium (S. Typhimurium) requires Salmonella pathogenicity island 2 (SPI-2) to survive and replicate within macrophages. High expression of many SPI-2 genes during the entire intracellular growth period within macrophages is essential, as it contributes to the formation of Salmonella-containing vacuole and bacterial replication. However, the regulatory mechanisms underlying the sustained induction of SPI-2 within macrophages are not fully understood. Here, we revealed a time-dependent regulation of SPI-2 expression mediated by a novel regulator PagR (STM2345) in response to the low Mg2+ and low phosphate (P-i) signals, which ensured the high induction of SPI-2 during the entire intramacrophage growth period. Deletion of pagR results in reduced bacterial replication in macrophages and attenuation of systemic virulence in mice. The effects of pagR on virulence are dependent on upregulating the expression of slyA, a regulator of SPI-2. At the early (0-4 hr) and later (after 4 hr) stage post-infection of macrophages, pagR is induced by the low P-i via PhoB/R two-component systems and low Mg2+ via PhoP/Q systems, respectively. Collectively, our findings revealed that the PagR-mediated regulatory mechanism contributes to the precise and sustained activation of SPI-2 genes within macrophages, which is essential for S. Typhimurium systemic virulence.

为了建立全身性感染，鼠伤寒沙门氏菌（S. Typhimurium）需要沙门氏菌致病岛2（SPI - 2）在巨噬细胞内生存和复制。在巨噬细胞内整个细胞内生长期间，许多SPI - 2基因的高表达是必不可少的，因为它有助于含沙门氏菌液泡的形成和细菌复制。然而，巨噬细胞内SPI - 2持续诱导的调控机制尚未完全清楚。在此，我们揭示了一种由新型调节因子PagR（STM2345）介导的SPI - 2表达的时间依赖性调控，它响应低镁离子（Mg²⁺）和低磷酸盐（P - i）信号，确保了在巨噬细胞内整个生长期间SPI - 2的高诱导。pagR的缺失导致细菌在巨噬细胞内复制减少以及在小鼠中的全身性毒力减弱。pagR对毒力的影响依赖于上调slyA的表达，slyA是SPI - 2的一个调节因子。在巨噬细胞感染后的早期（0 - 4小时）和后期（4小时后）阶段，pagR分别由低磷酸盐通过PhoB/R双组分系统和低镁离子通过PhoP/Q系统诱导。总之，我们的研究结果表明，PagR介导的调控机制有助于巨噬细胞内SPI - 2基因的精确和持续激活，这对鼠伤寒沙门氏菌的全身性毒力至关重要。