title: Contribution of Secreted NADase and Streptolysin O to the Pathogenesis of Epidemic Serotype M1 Streptococcus pyogenes Infections.
abstract: Streptococcus pyogenes secretes many toxins that facilitate human colonization, invasion, and dissemination. NADase (SPN) and streptolysin O (SLO) are two toxins that play important roles in pathogenesis. We previously showed that increased production of SPN and SLO in epidemic serotype M1 and M89 S. pyogenes strains is associated with rapid intercontinental spread and enhanced virulence. The biological functions of SPN and SLO have been extensively studied using eukaryotic cell lines, but the relative contribution of each of these two toxins to pathogenesis of epidemic M1 or M89 strains remains unexplored. Herein, using a genetically representative epidemic M1 strain and a panel of isogenic mutant derivative strains, we evaluated the relative contributions of SPN and SLO toxins to virulence in mouse models of necrotizing myositis, bacteremia, and skin and soft tissue infection. We found that isogenic mutants lacking SPN, SLO, and both toxins are equally impaired in ability to cause necrotizing myositis. In addition, mutants lacking either SPN or SLO are significantly attenuated in the bacteremia and soft tissue infection models, and the mutant strain lacking production of both toxins is further attenuated. The mutant strain lacking both SPN and SLO production is severely attenuated in ability to resist killing by human polymorphonuclear leukocytes. We conclude that both SPN and SLO contribute significantly to S. pyogenes pathogenesis in these virulence assays.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas.
authors.forename: Luchang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.affiliation: Department of Biosciences, Rice University, Houston, Texas.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Lee
authors.affiliation: Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.
authors.forename: Adeline R
authors.initials: AR
authors.lastname: Porter
authors.affiliation: Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.
authors.forename: Frank R
authors.initials: FR
authors.lastname: DeLeo
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas. Electronic address: jmmusser@houstonmethodist.org.
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D057131:Immune Evasion; D050296:Microbial Viability; D009154:Mutation / Q000235:genetics; D009244:NAD+ Nucleosidase / Q000378:metabolism*; D009504:Neutrophils / Q000382:microbiology; D010641:Phenotype; D012703:Serotyping; D013290:Streptococcal Infections / Q000453:epidemiology* / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000145:classification* / Q000472:pathogenicity*; D013301:Streptolysins / Q000378:metabolism*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D013301:Streptolysins; C025964:streptolysin O; D009244:NAD+ Nucleosidase