The transcriptional regulator VarN contributes to Salmonella Typhimurium growth in macrophages and virulence in mice

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major intracellular pathogen of humans and animals and its survival and growth in macrophages is essential for its pathogenicity. The S. Typhimurium genome encodes more than 50 putative regulatory proteins, but their involvement in pathogenicity and their regulatory roles are largely unknown. In this study, we investigated the biological function of the S. Typhimurium STM4320 gene (named varN), which encodes a putative MerR family transcriptional regulator. We found that varN is upregulated 2.6- to 6.8-fold after S. Typhimurium enters murine macrophages. A varN mutant reduced S. Typhimurium growth in murine macrophages and attenuated virulence in mice. Moreover, we showed that deletion of varN decreased the transcription of Salmonella pathogenicity island-2 (SPI-2) genes, which are required for S. Typhimurium growth in macrophages, indicative of the positive regulation of SPI-2 by VarN. We confirmed that the virulence defects of the varN mutant are entirely dependent on its regulation of SPI-2. Thus, our results revealed that VarN is a novel activator of the expression of SPI-2 genes and contributes to S. Typhimurium growth in macrophages and virulence in mice. Our findings provide a significant example of how a putative regulatory protein facilitates S. Typhimurium pathogenicity.