Abstract
The peroxide regulator (PerR) is a ferric uptake repressor-like protein, which is involved in adaptation to oxidative stress and iron homeostasis in group A streptococcus. A perR mutant is attenuated in surviving in human blood, colonization of the pharynx, and resistance to phagocytic clearance, indicating that the PerR regulon affects both host environment adaptation and immune escape. Sda1 is a phage-associated DNase which promotes M1T1 group A streptococcus escaping from phagocytic cells by degrading DNA-based neutrophil extracellular traps. In the present study, we found that the expression of sda1 is up-regulated under oxidative conditions in the wild-type strain but not in the perR mutant. A gel mobility shift assay showed that the recombinant PerR protein binds the sda1 promoter. In addition, mutation of the conserved histidine residue in the metal binding site of PerR abolished sda1 expression under hydrogen peroxide treatment conditions, suggesting that PerR is directly responsible for the sda1 expression under oxidative stress. Our results reveal PerR-dependent sda1 expression under oxidative stress, which may aid innate immune escape of group A streptococcus.
Highlights
Streptococcus pyogenes is a facultative Gram-positive human pathogen which causes mild to severe infectious diseases including pharyngitis, cellulitis, necrotizing fasciitis, and toxic shock syndrome [1,2]
Expression of DNase genes in the perR mutant A perR mutant is more resistant to oxidative stresses in vitro, but more susceptible to phagocytic cell clearance when compared to the wild-type strain [3,10]
The peroxide response regulator (PerR) of GAS is important for bacterial survival in human blood, colonization of the pharynx, and resistance to phagocytic clearance, indicating that the peroxide regulator (PerR) regulon is crucial for GAS to establish successful infections [3,10,11]
Summary
Streptococcus pyogenes (group A streptococcus, GAS) is a facultative Gram-positive human pathogen which causes mild to severe infectious diseases including pharyngitis, cellulitis, necrotizing fasciitis, and toxic shock syndrome [1,2]. It lacks catalase, GAS has developed other defense mechanisms against oxidative stress, including NADH oxidase, superoxide dismutase, peroxidases, and Dps-like peroxide resistance protein [3,4]. The perR mutant is more susceptible to phagocytic cell clearance [10], indicating that the PerR regulon contributes to immune escape. Transcriptome analysis further showed that PerR regulates peroxide detoxifying enzyme expression, and coordinates DNA and protein metabolisms and DNA repair system activity, which may contribute to GAS virulence and adaptation to the host environment [5,11]
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