title: Parameters governing invasive disease propensity of non-M1 serotype group A streptococci.
abstract: Group A Streptococcus (GAS) causes rare but life-threatening syndromes of necrotizing fasciitis and toxic shock-like syndrome in humans. The GAS serotype M1T1 clone has globally disseminated, and mutations in the control of virulence regulatory sensor kinase (covRS) operon correlate with severe invasive disease. Here, a cohort of non-M1 GAS was screened to determine whether mutation in covRS triggers systemic dissemination in divergent M serotypes. A GAS disease model defining parameters governing invasive propensity of differing M types is proposed. The vast majority of GAS infection is benign. Nonetheless, many divergent M types possess limited capacity to cause invasive infection. M1T1 GAS readily switch to a covRS mutant form that is neutrophil resistant and frequently associated with systemic infection. Whilst non-M1 GAS are shown in this study to less frequently accumulate covRS mutations in vivo, such mutants are isolated from invasive infections and exhibit neutrophil resistance and enhanced virulence. The reduced capacity of non-M1 GAS to switch to the hypervirulent covRS mutant form provides an explanation for the comparatively less frequent isolation of non-M1 serotypes from invasive human infections.
authors.affiliation: School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Maamary
authors.forename: Martina L
authors.initials: ML
authors.lastname: Sanderson-Smith
authors.forename: Ramy K
authors.initials: RK
authors.lastname: Aziz
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.forename: Fiona C
authors.initials: FC
authors.lastname: McKay
authors.forename: Jason D
authors.initials: JD
authors.lastname: McArthur
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Kirk
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Cork
authors.forename: Rachael J
authors.initials: RJ
authors.lastname: Keefe
authors.forename: Rita G
authors.initials: RG
authors.lastname: Kansal
authors.forename: Hongmin
authors.initials: H
authors.lastname: Sun
authors.forename: William L
authors.initials: WL
authors.lastname: Taylor
authors.forename: Gursharan S
authors.initials: GS
authors.lastname: Chhatwal
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004269:DNA, Bacterial / Q000032:analysis*; D018450:Disease Progression; D005816:Genetic Complementation Test; D000071677:Histidine Kinase; D006801:Humans; D057131:Immune Evasion / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D013297:Streptococcus pyogenes / Q000472:pathogenicity / Q000502:physiology*; D014774:Virulence / Q000235:genetics
chemical_list: D004269:DNA, Bacterial; D047908:Intracellular Signaling Peptides and Proteins; C534547:CovS protein, Streptococcus pyogenes; D000071677:Histidine Kinase
references.citation: BMC Infect Dis. 2004 Dec 16;4(1):60
references.pmid: 15601476
references.citation: Mol Microbiol. 1998 Oct;30(1):209-19
references.pmid: 9786197
references.citation: Infect Immun. 2004 Jan;72(1):364-70
references.pmid: 14688117
references.citation: Infect Immun. 2001 Nov;69(11):6683-8
references.pmid: 11598038
references.citation: Jpn J Exp Med. 1966 Apr;36(2):161-74
references.pmid: 5297293
references.citation: Nat Med. 2002 Dec;8(12):1398-404
references.pmid: 12436116
references.citation: J Infect Dis. 2009 Aug 15;200(4):555-63
references.pmid: 19591574
references.citation: Mol Microbiol. 2001 Jan;39(2):512-9
references.pmid: 11136470
references.citation: Clin Microbiol Rev. 2000 Jul;13(3):470-511
references.pmid: 10885988
references.citation: Rev Infect Dis. 1988 Jul-Aug;10 Suppl 2:S274-6
references.pmid: 3055197
references.citation: J Biol Chem. 2006 Sep 8;281(36):25965-71
references.pmid: 16822869
references.citation: EMBO J. 1998 Nov 2;17(21):6263-75
references.pmid: 9799235
references.citation: J Infect Dis. 2000 Dec;182(6):1702-11
references.pmid: 11069243
references.citation: J Infect Dis. 1997 Jul;176(1):177-82
references.pmid: 9207364
references.citation: Infect Immun. 1995 Mar;63(3):994-1003
references.pmid: 7868273
references.citation: Nat Med. 2007 Aug;13(8):981-5
references.pmid: 17632528
references.citation: PLoS Pathog. 2006 Jan;2(1):e5
references.pmid: 16446783
references.citation: Emerg Infect Dis. 2008 Oct;14(10):1511-7
references.pmid: 18826812
references.citation: Curr Biol. 2006 Feb 21;16(4):396-400
references.pmid: 16488874
references.citation: Science. 2004 Aug 27;305(5688):1283-6
references.pmid: 15333838
references.citation: J Infect Dis. 2005 Sep 1;192(5):771-82
references.pmid: 16088826
references.citation: Trends Microbiol. 2005 Jul;13(7):308-13
references.pmid: 15936195
references.citation: J Bacteriol. 2003 Sep;185(17):5166-74
references.pmid: 12923089
references.citation: J Bacteriol. 2005 May;187(10):3311-8
references.pmid: 15866915
references.citation: J Clin Microbiol. 1988 Aug;26(8):1539-42
references.pmid: 3049658
references.citation: Microbiology (Reading). 2002 Dec;148(Pt 12):3933-3945
references.pmid: 12480897
references.citation: FASEB J. 2006 Aug;20(10):1745-7
references.pmid: 16790522
references.citation: J Infect Dis. 2001 Apr 1;183(7):1043-54
references.pmid: 11237829
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1679-84
references.pmid: 15668390
references.citation: Infect Immun. 2000 Nov;68(11):6362-9
references.pmid: 11035746
references.citation: Mol Microbiol. 2004 Jan;51(1):123-34
references.pmid: 14651616
references.citation: J Infect Dis. 2006 Jun 15;193(12):1677-84
references.pmid: 16703511
references.citation: J Clin Invest. 1998 Aug 1;102(3):550-60
references.pmid: 9691092
references.citation: PLoS Pathog. 2010 Apr 01;6(4):e1000832
references.pmid: 20368967
references.citation: Trends Microbiol. 2007 Jul;15(7):318-25
references.pmid: 17524649
references.citation: PLoS One. 2008;3(12):e4102
references.pmid: 19116661
references.citation: FASEB J. 2008 Aug;22(8):2715-22
references.pmid: 18467595
references.citation: Infect Immun. 1999 Oct;67(10):5495-9
references.pmid: 10496938
references.citation: Infect Immun. 2000 Jul;68(7):4245-54
references.pmid: 10858242
references.citation: Infect Immun. 1997 Jan;65(1):64-71
references.pmid: 8975893
references.citation: Lancet Infect Dis. 2005 Nov;5(11):685-94
references.pmid: 16253886
references.citation: J Infect Dis. 1992 Aug;166(2):374-82
references.pmid: 1634809