title: Asymptomatic carriage of group A streptococcus is associated with elimination of capsule production.
abstract: Humans commonly carry pathogenic bacteria asymptomatically, but despite decades of study, the underlying molecular contributors remain poorly understood. Here, we show that a group A streptococcus carriage strain contains a frameshift mutation in the hasA gene resulting in loss of hyaluronic acid capsule biosynthesis. This mutation was repaired by allelic replacement, resulting in restoration of capsule production in the isogenic derivative strain. The "repaired" isogenic strain was significantly more virulent than the carriage strain in a mouse model of necrotizing fasciitis and had enhanced growth ex vivo in human blood. Importantly, the repaired isogenic strain colonized the mouse oropharynx with significantly greater bacterial burden and had significantly reduced ability to internalize into cultured epithelial cells than the acapsular carriage strain. We conducted full-genome sequencing of 81 strains cultured serially from 19 epidemiologically unrelated human subjects and discovered the common theme that mutations negatively affecting capsule biosynthesis arise in vivo in the has operon. The significantly decreased capsule production is a key factor contributing to the molecular détente between pathogen and host. Our discoveries suggest a general model for bacterial pathogens in which mutations that downregulate or ablate virulence factor production contribute to carriage.
authors.affiliation: Section of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist, Houston, Texas, USA arflores@bcm.edu.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Flores
authors.affiliation: Section of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist, Houston, Texas, USA.
authors.forename: Brittany E
authors.initials: BE
authors.lastname: Jewell
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist, Houston, Texas, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.affiliation: Department of Infectious Diseases, Division of Internal Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Shelburne
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist, Houston, Texas, USA.
authors.forename: Nahuel
authors.initials: N
authors.lastname: Fittipaldi
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist, Houston, Texas, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Beres
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist, Houston, Texas, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009876:Operon / Q000235:genetics; D009960:Oropharynx / Q000378:metabolism / Q000382:microbiology; D013290:Streptococcal Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D013291:Streptococcus / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D037521:Virulence Factors; D006820:Hyaluronic Acid