Evolution of group A streptococci: impact on virulence capacity

Streptococcus pyogenes (group A Streptococcus; GAS) is a Gram-positive bacterial pathogen that colonises the epithelia and mucosa of humans. Normally causing mild or asymptomatic skin and throat infections, GAS are opportunistic pathogens also capable of causing a range of diseases from pharyngitis and impetigo to the rare but life-threatening conditions of necrotizing fasciitis and toxic shock-like syndrome. The incidence of GAS infection in Western populations declined throughout the 20th century, however the last 30 years has witnessed a resurgence of severe GAS infections, paralleled by the emergence of dominant GAS clones, in otherwise healthy host populations. The hyperinvasive GAS M1T1 clone arose in the mid-1980s in the Rocky Mountains region of the USA and has since disseminated worldwide. While much is understood regarding the capacity of this pathogen to cause disease, much less is known of the precise molecular evolutionary events selecting for it’s emergence. Examination of a World Health Organization strain collection of serotype M1 GAS revealed that recombinatorial replacement of a 36 kilobase genome segment from serotype M12 GAS and acquisition of the bacteriophage encoded DNase Sda1 occurred relatively early in the evolutionary sequence and enhanced the virulence of the M1T1 precursor. The more recent acquisition of the phage-encoded superantigen SpeA contributes to immune dysregulation and is likely to have provided a selection advantage for the global dissemination of the M1T1 clone within Western populations. This study provides an exemplar for the evolution and emergence of virulent clones from microbial populations existing commensally or causing only benign infection. In comparison with the highly virulent GAS M1T1 clone, many divergent M types possess a limited capacity to cause invasive infection. Nonetheless, GAS diseases are endemic among many developing communities, and unlike Western populations, infections in developing populations are associated with a variety of M serotypes. The trigger for invasive M1T1 disease has been linked to mutations in the control of virulence regulatory sensor kinase (covRS) operon, conferring a hyperinvasive neutrophil resistant phenotype during local infection. Examination of a cohort of non-M1 isolates revealed that divergent M serotypes less frequently accumulate covRS mutations in vivo. However, such mutants are isolated from invasive infections, albeit less frequently, and exhibit neutrophil resistance and enhanced virulence. A GAS disease model defining parameters governing invasive propensity of differing M types is proposed. The reduced capacity of non-M1 GAS to switch to the hyperinvasive covRS mutant form provides an explanation for the comparatively less frequent isolation of non-M1 serotypes from invasive human infections. Scarlet fever is a toxin-mediated complication of GAS pharyngitis that was a significant health burden prior to the antibiotic era. While scarlet fever is commonly considered a rare disease today, this condition has been a notifiable disease to the Hong Kong Department of Health since World War II. In spring-summer 2011 there was a rapid surge in the number of scarlet fever cases reported in Hong Kong. The outbreak was multiclonal in nature and associated with multi-resistant GAS genotype emm12 strains. A phenotypic comparison of two non-clonal outbreak strains and the M1T1 GAS clone was undertaken. All isolates contained intact covRS loci and displayed equivalent virulence in a humanized plasminogen mouse model of subcutaneous infection. The virulence of emm12 outbreak strains was unlinked to mutations in covRS. Low frequency switching to the invasive covRS mutant form was attributed to limited Sda1 expression and diminished up-regulation of hyaluronic capsule in the emm12 background. This observation was consistent with the relatively low number of invasive complications associated with the Hong Kong outbreak. The predilection of emm12 outbreak strains for scarlet fever may be the result of recently acquired bacteriophage-encoded toxins, however the acquisition of toxin- or resistance-encoding elements does not exclusively account for the 2011 scarlet fever outbreak. While the clinical end-point of infection is largely predetermined by a number of bacterial factors, the epidemiology of GAS infections is also shaped by a cooperation of environmental factors, bacterial features and host immune function.