A Single Amino Acid Replacement in the Sensor Kinase LiaS Contributes to a Carrier Phenotype in Group A Streptococcus.
Despite the high frequency of asymptomatic carriage of bacterial pathogens, we understand little about the bacterial molecular genetic underpinnings of this phenomenon. To obtain new information about the molecular genetic mechanisms underlying carriage of group A Streptococcus (GAS), we performed whole-genome sequencing of GAS strains recovered from a single individual during acute pharyngitis and subsequent asymptomatic carriage. We discovered that compared to the initial infection isolate, the strain recovered during asymptomatic carriage contained three single nucleotide polymorphisms, one of which was in a highly conserved region of a gene encoding a sensor kinase, liaS, resulting in an arginine-to-glycine amino acid replacement at position 135 of LiaS (LiaS(R135G)). Using gene replacement, we demonstrate that introduction of the carrier allele (liaS(R135G)) into a serotype-matched invasive strain increased mouse nasopharyngeal colonization and adherence to cultured human epithelial cells. The carrier mutation also resulted in a reduced ability to grow in human blood and reduced virulence in a mouse model of necrotizing fasciitis. Repair of the mutation in the GAS carrier strain restored virulence and decreased adherence to cultured human epithelial cells. We also provide evidence that the carrier mutation alters the GAS transcriptome, including altered transcription of GAS virulence genes, providing a potential mechanism for the pleiotropic phenotypic effects. Our data obtained using isogenic strains suggest that the liaS(R135G) mutation in the carrier strain contributes to the transition from disease to asymptomatic carriage and provides new information about this poorly described regulatory system in GAS.
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 Hospital System, Houston, Texas, USA arflores@bcm.edu.
Anthony R
AR
Flores
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 Hospital System, Houston, Texas, USA.
Brittany E
BE
Jewell
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 Hospital System, Houston, Texas, USA.
Dedipya
D
Yelamanchili
Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist Hospital System, Houston, Texas, USA.
Randall J
RJ
Olsen
Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Department of Pathology and Genomic Medicine, Houston Methodist Hospital System, Houston, Texas, USA.
James M
JM
Musser
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D058070:Asymptomatic Diseases; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002353:Carrier State / Q000382:microbiology*; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010641:Phenotype; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013290:Streptococcal Infections / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics
D001426:Bacterial Proteins; D011494:Protein Kinases