Prophage exotoxins enhance colonization fitness in epidemic scarlet fever-causingStreptococcus pyogenes

• DOI: 10.1101/2020.05.17.095000
• Publication Date: 2020-05-18T11:26:14Z
• Authors: Stephan Brouwer; Timothy C. Barnett; Diane Ly; Katherine J. Kasper; David M.P. De Oli...; Tania Rivera-Hern...; Amanda J. Cork; Liam McIntyre; Magnus G. Jespersen; Johanna Richter; Benjamin L. Schulz; Gordon Dougan; Victor Nizet; Kwok-Yung Yuen; Yuanhai You; John K. McCormick; Martina L. Sander...; Mark R. Davies; Mark J. Walker
• Keywords: Male; 0301 basic medicine; /82/29; Erythrocytes; /631/326/1320; Prophages; General Physics and Astronomy; Gene; /38/70; /13/1; /38/1; Pathology; /38/22; 3100 Physics and Astronomy; Immunology and Microbiology; Superantigen; 0303 health sciences; Superantigens; Bartonella Infections and Zoonotic Potential; Virulence; Q; article; Life Sciences; 1600 Chemistry; Scarlet fever; Glutathione; 3. Good health; Streptolysins; /38/77; Medicine; Female; /38/39; Global Burden of Group A Streptococcal Diseases; Molecular Mechanisms of Inflammasome Activation and Regulation; Staphylococcus aureus; 1300 Biochemistry; Scarlet Fever; Virulence Factors; Streptococcus pyogenes; Science; 610; Exotoxins; Genetics and Molecular Biology; Mice, Transgenic; /13/106; Microbiology; Article; Cell Line; /38/91; /82/80; 03 medical and health sciences; /14/34; Bacterial Proteins; Biochemistry, Genetics and Molecular Biology; Health Sciences; Genetics; Escherichia coli; Animals; Humans; Bacteriophage; Molecular Biology; Biology; /82/83; Bacteria; /692/420/254; Public Health, Environmental and Occupational Health; General Chemistry; /64/110; Mice, Inbred C57BL; FOS: Biological sciences; General Biochemistry; Mutation; /14/63; Pharynx; Parasitology; Prophage

AbstractThe re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 (emm12)Streptococcus pyogenes(group AStreptococcus, 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 comprehensive 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 optimal growth in human blood, confers resistance to neutrophil killing, and degrades neutrophil extracellular traps (NETs). 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 etiology and pathogenesis of scarlet fever-causing GAS mediated by phage ΦHKU.vir exotoxins.