Prophage exotoxins enhance colonization fitness in epidemic scarlet fever-causing Streptococcus pyogenes

Stephan Brouwer; Timothy C Barnett; Diane Ly; Katherine J Kasper; David M P De Oliveira; Tania Rivera-Hernandez; 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 Sanderson-Smith; Mark R Davies; Mark J Walker

doi:10.1038/s41467-020-18700-5

Prophage exotoxins enhance colonization fitness in epidemic scarlet fever-causing Streptococcus pyogenes

Nat Commun. 2020 Oct 6;11(1):5018. doi: 10.1038/s41467-020-18700-5.

Authors

Stephan Brouwer^#¹, Timothy C Barnett^#^{1

2}, Diane Ly^{3

4}, Katherine J Kasper⁵, David M P De Oliveira¹, Tania Rivera-Hernandez¹, Amanda J Cork¹, Liam McIntyre⁶, Magnus G Jespersen⁶, Johanna Richter¹, Benjamin L Schulz¹, Gordon Dougan^{7

8}, Victor Nizet⁹, Kwok-Yung Yuen^{10

11

12}, Yuanhai You¹³, John K McCormick^{5

14}, Martina L Sanderson-Smith^{3

4}, Mark R Davies^{1

6}, Mark J Walker¹⁵

Affiliations

¹ Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, Australia.
² Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.
³ Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
⁴ Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia.
⁵ Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
⁶ Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.
⁷ The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
⁸ Department of Medicine, University of Cambridge, Cambridge, UK.
⁹ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
¹⁰ State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China.
¹¹ Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China.
¹² Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, Hong Kong, China.
¹³ State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Centre for Disease Control and Prevention, Beijing, 102206, China.
¹⁴ Lawson Health Research Institute, London, ON, Canada.
¹⁵ Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, Australia. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bacterial Proteins / pharmacology
Cell Line
Erythrocytes / drug effects
Exotoxins / genetics
Exotoxins / metabolism*
Female
Glutathione / metabolism
Humans
Male
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Pharynx / cytology
Prophages / genetics*
Scarlet Fever / epidemiology
Scarlet Fever / microbiology
Streptococcus pyogenes / genetics
Streptococcus pyogenes / pathogenicity*
Streptococcus pyogenes / virology*
Streptolysins / pharmacology
Superantigens / genetics
Superantigens / metabolism

Substances

Bacterial Proteins
Exotoxins
Streptolysins
Superantigens
streptolysin O
Glutathione

Abstract

Publication types

MeSH terms

Substances

Grants and funding