Streptococcal arginine deiminase system defences macrophage bactericidal effect mediated by XRE family protein XtrSs.

The arginine deiminase system (ADS) has been identified in various bacteria and functions to supplement energy production and enhance biological adaptability. The current understanding of the regulatory mechanism of ADS and its effect on bacterial pathogenesis is still limited. Here, we found that the XRE family transcriptional regulator XtrSs negatively affected <italic>Streptococcus suis</italic> virulence and significantly repressed ADS transcription when the bacteria were incubated in blood. Electrophoretic mobility shift (EMSA) and lacZ fusion assays further showed that XtrSs directly bind the promoter of ArgR, an acknowledged positive regulator of bacterial ADS, to repress ArgR transcription. Moreover, we provided compelling evidence that <italic>S. suis</italic> could utilize arginine via ADS to adapt to acid stress, while Δ<italic>xtrSs</italic> enhanced this acid resistance by upregulating the ADS operon. Moreover, whole ADS-knockout <italic>S. suis</italic> increased arginine and antimicrobial NO in the infected macrophage cells, decreased intracellular survival, and even caused significant attenuation of bacterial virulence in a mouse infection model, while Δ<italic>xtrSs</italic> consistently presented the opposite results. Our experiments identified a novel ADS regulatory mechanism in <italic>S. suis</italic>, whereby XtrSs regulated ADS to modulate NO content in macrophages, promoting <italic>S. suis</italic> intracellular survival. Meanwhile, our findings provide a new perspective on how <italic>Streptococci</italic> evade the host’s innate immune system. [ABSTRACT FROM AUTHOR]