title: Increased Pilus Production Conferred by a Naturally Occurring Mutation Alters Host-Pathogen Interaction in Favor of Carriage in Streptococcus pyogenes.
abstract: Studies of the human pathogen group AStreptococcus(GAS) define the carrier phenotype to be an increased ability to adhere to and persist on epithelial surfaces and a decreased ability to cause disease. We tested the hypothesis that a single amino acid change (Arg135Gly) in a highly conserved sensor kinase (LiaS) of a poorly defined GAS regulatory system contributes to a carrier phenotype through increased pilus production. When introduced into anemmserotype-matched invasive strain, the carrier allele (the gene encoding the LiaS protein with an arginine-to-glycine change at position 135 [liaSR135G]) recapitulated a carrier phenotype defined by an increased ability to adhere to mucosal surfaces and a decreased ability to cause disease. Gene transcript analyses revealed that theliaSmutation significantly altered transcription of the genes encoding pilus in the presence of bacitracin. Elimination of pilus production in the isogenic carrier mutant decreased its ability to colonize the mouse nasopharynx and to adhere to and be internalized by cultured human epithelial cells and restored the virulence phenotype in a mouse model of necrotizing fasciitis. We also observed significantly reduced survival of the isogenic carrier mutant compared to that of the parental invasive strain after exposure to human neutrophils. Elimination of pilus in the isogenic carrier mutant increased the level of survival after exposure to human neutrophils to that for the parental invasive strain. Together, our data demonstrate that the carrier mutation (liaSR135G) affects pilus expression. Our data suggest new mechanisms of pilus gene regulation in GAS and that the invasiveness associated with pilus gene regulation in GAS differs from the enhanced invasiveness associated with increased pilus production in other bacterial pathogens.
authors.affiliation: Section of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA arflores@bcm.edu.|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: Anthony R
authors.initials: AR
authors.lastname: Flores
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: 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: Concepcion
authors.initials: C
authors.lastname: Cantu
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA.
authors.forename: Kyler B
authors.initials: KB
authors.lastname: Pallister
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA.
authors.forename: Fermin E
authors.initials: FE
authors.lastname: Guerra
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana, USA.
authors.forename: Jovanka M
authors.initials: JM
authors.lastname: Voyich
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; D001422:Bacterial Adhesion; D002353:Carrier State / Q000382:microbiology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000382:microbiology; D005260:Female; D010861:Fimbriae, Bacterial / Q000235:genetics*; D020869:Gene Expression Profiling; D000071677:Histidine Kinase / Q000235:genetics*; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D050296:Microbial Viability; D020125:Mutation, Missense; D009305:Nasopharynx / Q000382:microbiology; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D001678:Organelle Biogenesis; D013290:Streptococcal Infections / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000472:pathogenicity* / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D000071677:Histidine Kinase
keywords: asymptomatic carriage; carrier; colonization; group A Streptococcus; pilus; sensor kinase