The Two-Component Signaling System VraSR ss Is Critical for Multidrug Resistance and Full Virulence in Streptococcus suis Serotype 2

has received increasing attention for its involvement in severe human infections worldwide as well as in multidrug resistance. Two-component signaling systems (TCSSs) play important roles in bacterial adaptation to various environmental stimuli. In this study, we identified a novel TCSS located in serotype 2 (SS2), designated VraSR , which is involved in bacterial pathogenicity and susceptibility to antimicrobials. Our data demonstrated that the gene, located upstream of , shared the same promoter with the TCSS genes, which was directly regulated by VraSR , as shown in electrophoretic mobility shift assays. Notably, YvqF and VraSR constitute a novel multidrug resistance module of SS2 that participates in resistance to certain groups of antimicrobials. Further analyses showed that VraSR inactivation significantly attenuated bacterial virulence in animal models, which, coupled with the significant activation of VraSR expression observed in host blood, strongly suggested that VraSR is an important regulator of SS2 pathogenicity. Indeed, RNA-sequencing analyses identified 106 genes that were differentially expressed between the wild-type and Δ strains, including genes involved in capsular polysaccharide (CPS) biosynthesis. Subsequent studies confirmed that VraSR indirectly regulated the transcription of CPS gene clusters and, thus, controlled the CPS thickness shown by transmission electron microscopy. Decreased CPS biosynthesis caused by deletion subsequently increased bacterial adhesion to epithelial cells and attenuated antiphagocytosis against macrophages, which partially clarified the pathogenic mechanism mediated by VraSR Taken together, our data suggest that the novel TCSS, VraSR , plays critical roles for multidrug resistance and full virulence in SS2.