title: M protein and hyaluronic acid capsule are essential for in vivo selection of covRS mutations characteristic of invasive serotype M1T1 group A Streptococcus.
abstract: The initiation of hyperinvasive disease in group A Streptococcus (GAS) serotype M1T1 occurs by mutation within the covRS two-component regulon (named covRS for control of virulence regulatory sensor kinase), which promotes resistance to neutrophil-mediated killing through the upregulation of bacteriophage-encoded Sda1 DNase. To determine whether other virulence factors contribute to this phase-switching phenomenon, we studied a panel of 10 isogenic GAS serotype M1T1 virulence gene knockout mutants. While loss of several individual virulence factors did not prevent GAS covRS switching in vivo, we found that M1 protein and hyaluronic acid capsule are indispensable for the switching phenotype, a phenomenon previously attributed uniquely to the Sda1 DNase. We demonstrate that like M1 protein and Sda1, capsule expression enhances survival of GAS serotype M1T1 within neutrophil extracellular traps. Furthermore, capsule shares with M1 protein a role in GAS resistance to human cathelicidin antimicrobial peptide LL-37. We conclude that a quorum of GAS serotype M1T1 virulence genes with cooperative roles in resistance to neutrophil extracellular killing is essential for the switch to a hyperinvasive phenotype in vivo.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Pence
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D016667:Bacterial Capsules / Q000737:chemistry / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D005260:Female; D000071677:Histidine Kinase; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D009154:Mutation; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D012097:Repressor Proteins / Q000235:genetics* / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; C432143:CsrR protein, Streptococcus pyogenes; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; D037521:Virulence Factors; C014689:streptococcal M protein; D006820:Hyaluronic Acid; C534547:CovS protein, Streptococcus pyogenes; D000071677:Histidine Kinase
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