Abstract
The re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 (emm12) Streptococcus pyogenes (group A Streptococcus, GAS) to cause scarlet fever has been linked epidemiologically to the presence of novel prophages, including prophage ΦHKU.vir encoding the secreted superantigens SSA and SpeC and the DNase Spd1. Here, we report the molecular characterization of ΦHKU.vir-encoded exotoxins. We demonstrate that streptolysin O (SLO)-induced glutathione efflux from host cellular stores is a previously unappreciated GAS virulence mechanism that promotes SSA release and activity, representing the first description of a thiol-activated bacterial superantigen. Spd1 is required for resistance to neutrophil killing. Investigating single, double and triple isogenic knockout mutants of the ΦHKU.vir-encoded exotoxins, we find that SpeC and Spd1 act synergistically to facilitate nasopharyngeal colonization in a mouse model. These results offer insight into the pathogenesis of scarlet fever-causing GAS mediated by prophage ΦHKU.vir exotoxins.
Highlights
The re-emergence of scarlet fever poses a new global public health threat
Potential triggers for these new scarlet fever epidemics remain unclear, but accumulating epidemiological evidence indicates that novel prophages and antibiotic resistance elements have played a significant role in the evolution, virulence and diversification of scarlet fever causing group A Streptococcus (GAS) strains in North-East Asia[4,15,16,17]
Detailed phylogenetic analyses of GAS outbreak isolates from mainland China and Hong Kong prove that the increase in scarlet fever cases was neither emm-type specific nor caused by the spread of a single scarlet fever producing clone
Summary
The re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 (emm12) Streptococcus pyogenes (group A Streptococcus, GAS) to cause scarlet fever has been linked epidemiologically to the presence of novel prophages, including prophage ΦHKU.vir encoding the secreted superantigens SSA and SpeC and the DNase Spd[1]. Investigating single, double and triple isogenic knockout mutants of the ΦHKU.vir-encoded exotoxins, we find that SpeC and Spd[1] act synergistically to facilitate nasopharyngeal colonization in a mouse model These results offer insight into the pathogenesis of scarlet fever-causing GAS mediated by prophage ΦHKU.vir exotoxins. Recent studies report GAS outbreak strains in other countries[11,12,13], heightening the need for global surveillance[14] Potential triggers for these new scarlet fever epidemics remain unclear, but accumulating epidemiological evidence indicates that novel prophages and antibiotic resistance elements have played a significant role in the evolution, virulence and diversification of scarlet fever causing GAS strains in North-East Asia[4,15,16,17]. Exotoxin-driven enhanced colonization provides an evidencebased hypothesis for the reemergence of scarlet fever globally
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