title: Intergenic Variable-Number Tandem-Repeat Polymorphism Upstream of rocA Alters Toxin Production and Enhances Virulence in Streptococcus pyogenes.
abstract: Variable-number tandem-repeat (VNTR) polymorphisms are ubiquitous in bacteria. However, only a small fraction of them has been functionally studied. Here, we report an intergenic VNTR polymorphism that confers an altered level of toxin production and increased virulence in Streptococcus pyogenes The nature of the polymorphism is a one-unit deletion in a three-tandem-repeat locus upstream of the rocA gene encoding a sensor kinase. S. pyogenes strains with this type of polymorphism cause human infection and produce significantly larger amounts of the secreted cytotoxins S. pyogenes NADase (SPN) and streptolysin O (SLO). Using isogenic mutant strains, we demonstrate that deleting one or more units of the tandem repeats abolished RocA production, reduced CovR phosphorylation, derepressed multiple CovR-regulated virulence factors (such as SPN and SLO), and increased virulence in a mouse model of necrotizing fasciitis. The phenotypic effect of the VNTR polymorphism was nearly the same as that of inactivating the rocA gene. In summary, we identified and characterized an intergenic VNTR polymorphism in S. pyogenes that affects toxin production and virulence. These new findings enhance understanding of rocA biology and the function of VNTR polymorphisms in S. pyogenes.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Luchang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.affiliation: Department of Infectious Diseases, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Horstmann
authors.affiliation: Department of Infectious Diseases, MD Anderson Cancer Center, Houston, Texas, USA.|Department of Genomic Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Shelburne
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA jmmusser@houstonmethodist.org.
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001483:Base Sequence; D004195:Disease Models, Animal; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D051379:Mice; D018598:Minisatellite Repeats; D009244:NAD+ Nucleosidase / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D013290:Streptococcal Infections / Q000382:microbiology / Q000401:mortality; D013297:Streptococcus pyogenes / Q000472:pathogenicity / Q000502:physiology*; D013301:Streptolysins / Q000096:biosynthesis* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; C474644:RocA protein, Streptococcus pyogenes; D013301:Streptolysins; D015534:Trans-Activators; C025964:streptolysin O; D009244:NAD+ Nucleosidase