Abstract
Streptococcus pyogenes (group A Streptococcus; GAS) is a widespread human pathogen and causes streptococcal toxic shock syndrome (STSS). STSS isolates have been previously shown to have high frequency mutations in the csrS/csrR (covS/covR) and/or rgg (ropB) genes, which are negative regulators of virulence. However, these mutations were found at somewhat low frequencies in emm1-genotyped isolates, the most prevalent STSS genotype. In this study, we sought to detect causal mutations of enhanced virulence in emm1 isolates lacking mutation(s) in the csrS/csrR and rgg genes. Three mutations associated with elevated virulence were found in the sic (a virulence gene) promoter, the csrR promoter, and the rocA gene (a csrR positive regulator). In vivo contribution of the sic promoter and rocA mutations to pathogenicity and lethality was confirmed in a GAS mouse model. Frequency of the sic promoter mutation was significantly higher in STSS emm1 isolates than in non-invasive STSS isolates; the rocA gene mutation frequency was not significantly different among STSS and non-STSS isolates. STSS emm1 isolates possessed a high frequency mutation in the sic promoter. Thus, this mutation may play a role in the dynamics of virulence and STSS pathogenesis.
Highlights
Group A Streptococcus (GAS) is one of the most common human pathogens and causes various infections, ranging from uncomplicated pharyngitis and skin infections to severe and even life-threatening manifestations, such as necrotizing fasciitis (NF) and bacteremia[1]
We hypothesized that there are other mutation(s) in these 44 emm1-genotyped streptococcal toxic shock syndrome (STSS) isolates responsible for enhanced virulence. We examined this hypothesis by identifying the STSS emm[1] isolates that significantly elevated the expression of important virulence genes such as scpA, sic, sda[1], nga, and ska as compared to non-invasive or non-STSS isolates to detect the novel mutations underpinning this enhanced virulence and demonstrate pathogenicity of these mutations in a GAS mouse model
In the 10 STSS emm[1] isolates, we found mutations in the sic promoter, the csrR promoter, or the rocA gene that conferred increased virulence gene expression
Summary
Group A Streptococcus (GAS) is one of the most common human pathogens and causes various infections, ranging from uncomplicated pharyngitis and skin infections to severe and even life-threatening manifestations, such as necrotizing fasciitis (NF) and bacteremia[1]. We examined this hypothesis by identifying the STSS emm[1] isolates that significantly elevated the expression of important virulence genes such as scpA, sic, sda[1], nga, and ska as compared to non-invasive or non-STSS isolates to detect the novel mutations underpinning this enhanced virulence and demonstrate pathogenicity of these mutations in a GAS mouse model. Such insights will shed light on the mechanisms underlying pathogenicity in STSS emm1-genotyped isolates
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