title: DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection.
abstract: Most invasive bacterial infections are caused by species that more commonly colonize the human host with minimal symptoms. Although phenotypic or genetic correlates underlying a bacterium's shift to enhanced virulence have been studied, the in vivo selection pressures governing such shifts are poorly understood. The globally disseminated M1T1 clone of group A Streptococcus (GAS) is linked with the rare but life-threatening syndromes of necrotizing fasciitis and toxic shock syndrome. Mutations in the GAS control of virulence regulatory sensor kinase (covRS) operon are associated with severe invasive disease, abolishing expression of a broad-spectrum cysteine protease (SpeB) and allowing the recruitment and activation of host plasminogen on the bacterial surface. Here we describe how bacteriophage-encoded GAS DNase (Sda1), which facilitates the pathogen's escape from neutrophil extracellular traps, serves as a selective force for covRS mutation. The results provide a paradigm whereby natural selection exerted by the innate immune system generates hypervirulent bacterial variants with increased risk of systemic dissemination.
authors.affiliation: School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.forename: Martina L
authors.initials: ML
authors.lastname: Sanderson-Smith
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Kirk
authors.forename: Anna
authors.initials: A
authors.lastname: Henningham
authors.forename: Jason D
authors.initials: JD
authors.lastname: McArthur
authors.forename: Katrin
authors.initials: K
authors.lastname: Dinkla
authors.forename: Ramy K
authors.initials: RK
authors.lastname: Aziz
authors.forename: Rita G
authors.initials: RG
authors.lastname: Kansal
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Simpson
authors.forename: John T
authors.initials: JT
authors.lastname: Buchanan
authors.forename: Gursharan S
authors.initials: GS
authors.lastname: Chhatwal
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D002470:Cell Survival; D003850:Deoxyribonuclease I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000382:microbiology; D010641:Phenotype; D012641:Selection, Genetic; D013290:Streptococcal Infections / Q000382:microbiology* / Q000473:pathology; D013297:Streptococcus pyogenes / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D003850:Deoxyribonuclease I; C493845:Sda1 protein, Streptococcus pyogenes