Supplementary Material for: Parameters Governing Invasive Disease Propensity of Non-M1 Serotype Group A Streptococci

Group A <i>Streptococcus</i> (GAS) causes rare but life-threatening syndromes of necrotizing fasciitis and toxic shock-like syndrome in humans. The GAS serotype M1T1 clone has globally disseminated, and mutations in the control of virulence regulatory sensor kinase (<i>covRS)</i> operon correlate with severe invasive disease. Here, a cohort of non-M1 GAS was screened to determine whether mutation in <i>covRS</i> triggers systemic dissemination in divergent M serotypes. A GAS disease model defining parameters governing invasive propensity of differing M types is proposed. The vast majority of GAS infection is benign. Nonetheless, many divergent M types possess limited capacity to cause invasive infection. M1T1 GAS readily switch to a <i>covRS</i> mutant form that is neutrophil resistant and frequently associated with systemic infection. Whilst non-M1 GAS are shown in this study to less frequently accumulate <i>covRS</i> mutations in vivo, such mutants are isolated from invasive infections and exhibit neutrophil resistance and enhanced virulence. The reduced capacity of non-M1 GAS to switch to the hypervirulent <i>covRS</i> mutant form provides an explanation for the comparatively less frequent isolation of non-M1 serotypes from invasive human infections.