Abstract
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.
Highlights
Streptococcus pneumoniae, usually a commensal in the upper human respiratory tract, is an etiologic agent of pneumonia, sepsis, and meningitis (Bogaert et al, 2004)
We found that after 5 min of serum exposure, these cps genes became up-regulated about ∼1.6–2.1-folds from their respective basal levels in both the wild type (WT) WU2 strain and its vncR mutant
Comparative sequence analysis of VncR exhibited a great similarity to the PhoB of other bacteria (Throup et al, 2000), which has been known to regulate the expression of various bacterial virulence factors (McCluskey et al, 2004)
Summary
Streptococcus pneumoniae, usually a commensal in the upper human respiratory tract, is an etiologic agent of pneumonia, sepsis, and meningitis (Bogaert et al, 2004). CPS shows a CPS Modulation by VncR via Lactoferrin differential expression profile between carriage pneumococci and planktonic pneumococci, capable of causing an invasive disease (Wu et al, 2016) Several proteins, such as CpsR (Wu et al, 2016), and ComE (Zheng et al, 2017) have been shown to play key roles in the regulation of cps genes, the underlying mechanism is poorly delineated. The synthesis of the other CPS types (3 and 37) is mediated by a single membrane-bound glycosyltransferase In these pneumococcal serotypes, the conserved sequences positioned at the 5 end of all the other loci, which are responsible for the transcription of regulatory proteins, are either absent (type 37) or mutated (type 3) (Moscoso and García, 2009). Type 3 pneumococcal cpsp is completely different from the other serotypes (Caimano et al, 1998), as a short 87 bp region embracing the cpsp is strictly conserved only among the Wzy serotypes (Moscoso and García, 2009)
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