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

Abstract

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.