Pneumococcal VncR Strain-Specifically Regulates Capsule Polysaccharide Synthesis

Capsular polysaccharides (CPS), a major virulence factor in Streptococcus pneumoniae, become thicker during blood invasion while not during asymptomatic nasopharyngeal colonization. However, the underlying mechanism controlling this differential pneumococcal CPS regulation remain unclear. Here, we show how VncR, the response regulator of the vancomycin resistance locus (vncRS operon), regulates CPS expression in vncR mutants in three serotype (type 2, 3, and 6B) backgrounds upon exposure to serum lactoferrin (LF). Comparative analysis of CPS levels in the wild type (WT) of three strains and their isogenic vncR mutants after LF exposure revealed a strain-specific alteration in CPS production. Consistently, VncR-mediated strain-specific CPS production is correlated with pneumococcal virulence, in vivo. Electrophoretic mobility-shift assay and co-immunoprecipitation revealed an interaction between VncR and the cps promoter (cpsp) in the presence of serum. In addition, in silico analysis uncovered this protein-DNA interaction, suggesting that VncR binds with the cpsp, and recognizes the strain-specific significance of the tandem repeats in cpsp. Taken together, the interaction of VncR and cpsp after serum exposure plays an essential role in regulating differential strain-specific CPS production, which subsequently determines strain-specific systemic virulence. This study highlights how host protein LF contributes to pneumococcal VncR-mediated CPS production. As CPS plays a significant role in immune evasion, these findings suggest that drugs designed to interrupt the VncR-mediated CPS production could help to combat pneumococcal infections.