Supplementary file 1_Salmonella typhimurium exploits macrophage-derived arginine as an intracellular signal for SPI-2 virulence gene activation.docx

However, how bacterial pathogens respond to host arginine metabolism remains poorly understood.</p>Results<p>We found that Salmonella Typhimurium (S. Tm) infection causes arginine accumulation in macrophages. This accumulation is associated with two concurrent mechanisms: enhanced arginine import via upregulation of the CAT2 transporter, and pathogen-mediated suppression of host iNOS expression.

S. Tm then exploits this accumulated arginine as an intracellular signal to upregulate virulence gene expression and promote its replication. Mechanistically, arginine activates the type III secretion system (T3SS) encoded by Salmonella pathogenicity island 2 (SPI-2) via the bacterial transcriptional regulator ArgR, which binds to the promoter of ssrA, the key regulator of SPI-2, in an arginine-dependent manner. Disruption of argR impairs S. Tm intracellular replication and attenuates virulence in mice.</p>Conclusions<p>These findings reveal that S. Tm co-opts the host’s arginine-mediated immune response by sensing macrophage-derived arginine as a signal to initiate its virulence program, revealing a pathogen adaptation strategy that links metabolic sensing to virulence activation.</p>