title: Defence against methylglyoxal in Group A Streptococcus: a role for Glyoxylase I in bacterial virulence and survival in neutrophils?
abstract: Methylglyoxal is a dicarbonyl compound that acts as a toxic electrophile in biological systems. Methylglyoxal is produced in certain bacteria as a byproduct of glycolysis through methylglyoxal synthase. Like many bacteria, Group A Streptococcus (GAS), a Gram-positive human pathogen responsible for a wide spectrum of diseases, uses a two-step glyoxalase system to remove methylglyoxal. However, bioinformatic analysis revealed that no homologue of methylglyoxal synthase is present in GAS, suggesting that the role of the glyoxalase system is to detoxify methylglyoxal produced by the host. In this study, we investigated the role of methylglyoxal detoxification in the pathogenesis of GAS. A mutant (5448ΔgloA), deficient in glyoxylase I (S-lactoylglutathione lyase), was constructed and tested for susceptibility to methylglyoxal, human neutrophil survival and virulence in a murine model of infection. 5448ΔgloA was more sensitive to methylglyoxal and was also more susceptible to human neutrophil killing. Inhibition of neutrophil myeloperoxidase rescued the gloA-deficient mutant indicating that this enzyme was required for methylglyoxal production. Furthermore, the 5448ΔgloA mutant was slower at disseminating into the blood in the murine model. These data suggest that neutrophils produce methylglyoxal as an antimicrobial agent during bacterial infection, and the glyoxalase system is part of the GAS defence against the innate immune system during pathogenesis.
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: May M
authors.initials: MM
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia y.ong@uq.edu.au.
authors.forename: Cheryl-lynn Y
authors.initials: CL
authors.lastname: Ong
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: McEwan
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D019295:Computational Biology / Q000379:methods; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D050296:Microbial Viability / Q000276:immunology; D008954:Models, Biological; D009154:Mutation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011765:Pyruvaldehyde / Q000378:metabolism*; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology* / Q000401:mortality; D013297:Streptococcus pyogenes / Q000472:pathogenicity / Q000502:physiology*; D014774:Virulence
chemical_list: D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase
keywords: GloA; Group A Streptococcus; Streptococcus pyogenes; aldehyde stress response; glyoxalase system; methylglyoxal