title: A naturally occurring single amino acid replacement in multiple gene regulator of group A Streptococcus significantly increases virulence.
abstract: Single-nucleotide polymorphisms (SNPs) are the most common source of genetic variation within a species; however, few investigations demonstrate how naturally occurring SNPs may increase strain virulence. We recently used group A Streptococcus as a model pathogen to study bacteria strain genotype-patient disease phenotype relationships. Whole-genome sequencing of approximately 800 serotype M59 group A Streptococcus strains, recovered during an outbreak of severe invasive infections across North America, identified a disproportionate number of SNPs in the gene encoding multiple gene regulator of group A Streptococcus (mga). Herein, we report results of studies designed to test the hypothesis that the most commonly occurring SNP, encoding a replacement of arginine for histidine at codon 201 of Mga (H201R), significantly increases virulence. Whole transcriptome analysis revealed that the H201R replacement significantly increased expression of mga and 54 other genes, including many proven virulence factors. Compared to the wild-type strain, a H201R isogenic mutant strain caused significantly larger skin lesions in mice. Serial quantitative bacterial culture and noninvasive magnetic resonance imaging also demonstrated that the isogenic H201R strain was significantly more virulent in a nonhuman primate model of joint infection. These findings show that the H201R replacement in Mga increases the virulence of M59 group A Streptococcus and provide new insight to how a naturally occurring SNP in bacteria contributes to human disease phenotypes.
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas; School of Biotechnology, School of Medicine and Health Sciences, Tecnológico de Monterrey, Monterrey, Mexico.
authors.forename: Misu
authors.initials: M
authors.lastname: Sanson
authors.affiliation: Department of Translational Imaging, MRI Core, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Brian E
authors.initials: BE
authors.lastname: O'Neill
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kachroo
authors.affiliation: Department of Translational Imaging, MRI Core, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Jeff R
authors.initials: JR
authors.lastname: Anderson
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Flores
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas.
authors.forename: Chandni
authors.initials: C
authors.lastname: Valson
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas.
authors.forename: Concepcion C
authors.initials: CC
authors.lastname: Cantu
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas.
authors.forename: Nishanth
authors.initials: N
authors.lastname: Makthal
authors.affiliation: Department of Translational Imaging, MRI Core, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Christof
authors.initials: C
authors.lastname: Karmonik
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Public Health Ontario, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nahuel
authors.initials: N
authors.lastname: Fittipaldi
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Kumaraswami
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas.
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Center for Molecular and Translational Human Infectious Diseases Research, Houston, Texas. Electronic address: rjolsen@houstonmethodist.org.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005260:Female; D016680:Genome, Bacterial; D006801:Humans; D007592:Joint Diseases / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D013290:Streptococcal Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D001426:Bacterial Proteins; C068267:mry protein, Streptococcus pyogenes