title: Polymorphisms in regulator of protease B (RopB) alter disease phenotype and strain virulence of serotype M3 group A Streptococcus.
abstract: Whole-genome sequencing of serotype M3 group A streptococci (GAS) from oropharyngeal and invasive infections in Ontario recently showed that the gene encoding regulator of protease B (RopB) is highly polymorphic in this population. To test the hypothesis that ropB is under diversifying selective pressure among all serotype M3 GAS strains, we sequenced this gene in 1178 strains collected from different infection types, geographic regions, and time periods. The results confirmed our hypothesis and discovered a significant association between mutant ropB alleles, decreased activity of its major regulatory target SpeB, and pharyngitis. Additionally, isoallelic strains with ropB polymorphisms were significantly less virulent in a mouse model of necrotizing fasciitis. These studies provide a model strategy for applying whole-genome sequencing followed by deep single-gene sequencing to generate new insight to the rapid evolution and virulence regulation of human pathogens.
authors.affiliation: Department of Pathology and Laboratory Medicine, The Methodist Hospital Research Institute, Houston, TX, USA. rjolsen@tmhs.org
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Laucirica
authors.forename: M Ebru
authors.initials: ME
authors.lastname: Watkins
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Feske
authors.forename: Jesus R
authors.initials: JR
authors.lastname: Garcia-Bustillos
authors.forename: Chau
authors.initials: C
authors.lastname: Vu
authors.forename: Concepcion
authors.initials: C
authors.lastname: Cantu
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Shelburne
authors.forename: Nahuel
authors.initials: N
authors.lastname: Fittipaldi
authors.forename: Muthiah
authors.initials: M
authors.lastname: Kumaraswami
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Shea
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Flores
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Beres
authors.forename: Maguerite
authors.initials: M
authors.lastname: Lovgren
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tyrrell
authors.forename: Androulla
authors.initials: A
authors.lastname: Efstratiou
authors.forename: Donald E
authors.initials: DE
authors.lastname: Low
authors.forename: Chris A
authors.initials: CA
authors.lastname: Van Beneden
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004195:Disease Models, Animal; D019115:Fasciitis, Necrotizing / Q000382:microbiology / Q000473:pathology; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010612:Pharyngitis / Q000382:microbiology* / Q000473:pathology; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D013290:Streptococcal Infections / Q000382:microbiology* / Q000473:pathology; D013297:Streptococcus pyogenes / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D050505:Mutant Proteins; C098249:RopB protein, Rhizobium leguminosarum; D037521:Virulence Factors