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

ABSTRACT

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