title: Consequences of the variability of the CovRS and RopB regulators among Streptococcus pyogenes causing human infections.
abstract: To evaluate the importance of covRS and ropB mutations in invasive disease caused by Group A Streptococci (GAS), we determined the sequence of the covRS and ropB genes of 191 isolates from invasive infections and pharyngitis, comprising a diverse set of emm types and multilocus sequence types. The production of SpeB and the activity of NAD glycohydrolase (NADase) and streptolysin S (SLS) were evaluated. The results support the acquisition of null covS alleles (predicted to eliminate protein function), resulting in downregulation of SpeB and upregulation of NADase and SLS, as a mechanism possibly contributing to higher invasiveness. Among the isolates tested, this mechanism was found to be uncommon (10% of invasive isolates) and was not more prevalent among clones with enhanced invasiveness (including M1T1) but occurred in diverse genetic backgrounds. In lineages such as emm64, these changes did not result in upregulation of NADase and SLS, highlighting the diversity of regulatory pathways in GAS. Despite abrogating SpeB production, null alleles in ropB were not associated with invasive infection. The covRS and ropB genes are under stabilising selection and no expansion of isolates carrying null alleles has been observed, suggesting that the presence of these regulators is important for overall fitness.
authors.affiliation: Instituto de Microbiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Friães
authors.affiliation: Instituto de Microbiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Pato
authors.affiliation: Instituto de Microbiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Melo-Cristino
authors.affiliation: Instituto de Microbiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Mario
authors.initials: M
authors.lastname: Ramirez
mesh_terms: D000483:Alleles; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004269:DNA, Bacterial / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D015536:Down-Regulation; D005098:Exotoxins / Q000378:metabolism; D000071677:Histidine Kinase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009244:NAD+ Nucleosidase / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013290:Streptococcal Infections / Q000382:microbiology* / Q000473:pathology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D013301:Streptolysins / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D005098:Exotoxins; D047908:Intracellular Signaling Peptides and Proteins; C098249:RopB protein, Rhizobium leguminosarum; D013301:Streptolysins; C027951:erythrogenic toxin; C026050:streptolysin S; C534547:CovS protein, Streptococcus pyogenes; D000071677:Histidine Kinase; D009244:NAD+ Nucleosidase