title: Streptolysin S inhibits neutrophil recruitment during the early stages of Streptococcus pyogenes infection.
abstract: In contrast to infection of superficial tissues, Streptococcus pyogenes infection of deeper tissue can be associated with a significantly diminished inflammatory response, suggesting that this bacterium has the ability to both promote and suppress inflammation. To examine this, we analyzed the behavior of an S. pyogenes mutant deficient in expression of the cytolytic toxin streptolysin S (SLS-) and evaluated events that occur during the first few hours of infection by using several models including injection of zebrafish (adults, larvae, and embryos), a transepithelial polymorphonuclear leukocyte (PMN) migration assay, and two-photon microscopy of mice in vivo. In contrast to wild-type S. pyogenes, the SLS- mutant was associated with the robust recruitment of neutrophils and significantly reduced lethal myositis in adult zebrafish. Similarly, the mutant was attenuated in embryos in its ability to cause lethality. Infection of larva muscle allowed an analysis of inflammation in real time, which revealed that the mutant had recruited PMNs to the infection site. Analysis of transepithelial migration in vitro suggested that SLS inhibited the host cells' production of signals chemotactic for neutrophils, which contrasted with the proinflammatory effect of an unrelated cytolytic toxin, streptolysin O. Using two-photon microscopy of mice in vivo, we showed that the extravasation of neutrophils during infection with SLS- mutant bacteria was significantly accelerated compared to infection with wild-type S. pyogenes. Taken together, these data support a role for SLS in the inhibition of neutrophil recruitment during the early stages of S. pyogenes infection.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., Box 8118, Saint Louis, MO 63110-1093, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Lin
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Loughman
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Zinselmeyer
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Miller
authors.forename: Michael G
authors.initials: MG
authors.lastname: Caparon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D051379:Mice; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D013290:Streptococcal Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013297:Streptococcus pyogenes; D013301:Streptolysins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015027:Zebrafish
chemical_list: D001426:Bacterial Proteins; D017382:Reactive Oxygen Species; D013301:Streptolysins; C026050:streptolysin S
references.citation: Infect Immun. 1990 Nov;58(11):3737-42
references.pmid: 1699898
references.citation: Mol Microbiol. 2005 May;56(3):681-95
references.pmid: 15819624
references.citation: Curr Protein Pept Sci. 2005 Feb;6(1):77-84
references.pmid: 15638770
references.citation: Mol Microbiol. 1998 Jan;27(2):337-46
references.pmid: 9484889
references.citation: J Infect Dis. 2001 Apr 1;183(7):1043-54
references.pmid: 11237829
references.citation: J Infect Dis. 2005 Jul 1;192(1):13-5
references.pmid: 15942888
references.citation: Infect Immun. 1998 Apr;66(4):1671-9
references.pmid: 9529097
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5879-84
references.pmid: 18375757
references.citation: Trends Microbiol. 2002 Dec;10(12):575-80
references.pmid: 12564994
references.citation: EMBO J. 2006 Oct 4;25(19):4628-37
references.pmid: 16977314
references.citation: Mol Microbiol. 1998 Oct;30(1):209-19
references.pmid: 9786197
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8289-94
references.pmid: 12060772
references.citation: Eur Cytokine Netw. 1997 Mar;8(1):83-90
references.pmid: 9110153
references.citation: J Cell Biol. 1988 Mar;106(3):761-71
references.pmid: 2450098
references.citation: Curr Protoc Cell Biol. 2001 Nov;Chapter 15:15.5.1-15.5.18
references.pmid: 18228332
references.citation: Mol Microbiol. 2001 Oct;42(1):145-57
references.pmid: 11679074
references.citation: Development. 1999 Sep;126(17):3735-45
references.pmid: 10433904
references.citation: Infect Immun. 1996 Feb;64(2):503-10
references.pmid: 8550199
references.citation: Infect Immun. 2004 Feb;72(2):623-8
references.pmid: 14742501
references.citation: Clin Infect Dis. 2005 Feb 1;40(3):410-4
references.pmid: 15668865
references.citation: FEMS Immunol Med Microbiol. 2004 Jan 15;40(1):1-9
references.pmid: 14734180
references.citation: Lancet. 2004 Feb 28;363(9410):696-703
references.pmid: 15001327
references.citation: Blood. 2006 Dec 15;108(13):3976-8
references.pmid: 16926288
references.citation: PLoS Pathog. 2006 Jan;2(1):e5
references.pmid: 16446783
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17786-91
references.pmid: 16306265
references.citation: Cell Microbiol. 2003 Sep;5(9):601-11
references.pmid: 12925130
references.citation: Infect Immun. 2003 Jan;71(1):446-55
references.pmid: 12496195
references.citation: J Biol Chem. 2001 Nov 9;276(45):41790-6
references.pmid: 11546819
references.citation: Blood. 2004 Sep 1;104(5):1291-7
references.pmid: 14996705
references.citation: Infect Immun. 2006 Apr;74(4):2436-41
references.pmid: 16552074
references.citation: J Infect Dis. 2005 Jul 1;192(1):107-16
references.pmid: 15942900
references.citation: Infect Immun. 2002 Oct;70(10):5730-9
references.pmid: 12228303
references.citation: J Clin Invest. 1991 Nov;88(5):1605-12
references.pmid: 1682344
references.citation: Blood. 2003 Nov 1;102(9):3238-40
references.pmid: 12869502
references.citation: Science. 2007 Jan 26;315(5811):509-13
references.pmid: 17255510
references.citation: Mol Immunol. 2004 Jan;40(11):773-83
references.pmid: 14687934
references.citation: Mol Microbiol. 2005 Sep;57(6):1545-56
references.pmid: 16135223
references.citation: J Infect Dis. 2005 Sep 1;192(5):783-90
references.pmid: 16088827
references.citation: Science. 2008 Aug 15;321(5891):970-4
references.pmid: 18703742
references.citation: Immunity. 2002 Dec;17(6):693-702
references.pmid: 12479816
references.citation: Immunity. 2008 Sep 19;29(3):487-96
references.pmid: 18718768
references.citation: Mol Microbiol. 2002 Oct;46(1):87-99
references.pmid: 12366833
references.citation: Mol Microbiol. 2001 Jan;39(2):236-47
references.pmid: 11136446
references.citation: APMIS. 1999 Dec;107(12):1051-9
references.pmid: 10660134
references.citation: J Infect Dis. 2007 Sep 1;196(5):755-62
references.pmid: 17674319
references.citation: Dev Dyn. 1995 Jul;203(3):253-310
references.pmid: 8589427
references.citation: Infect Immun. 1972 Oct;6(4):459-64
references.pmid: 4634952
references.citation: J Immunol. 2006 Jul 15;177(2):1221-8
references.pmid: 16818781
references.citation: Infect Immun. 2006 Nov;74(11):6108-17
references.pmid: 17057088
references.citation: J Leukoc Biol. 2006 Dec;80(6):1281-8
references.pmid: 16963624
references.citation: Infect Immun. 1991 May;59(5):1811-7
references.pmid: 2019444
references.citation: Infect Immun. 2002 Jul;70(7):3904-14
references.pmid: 12065534
references.citation: Mol Immunol. 2004 Jan;40(11):759-71
references.pmid: 14687933
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4658-63
references.pmid: 11296296
references.citation: J Exp Med. 1963 Aug 1;118:223-8
references.pmid: 14074386
references.citation: Infect Immun. 1992 Dec;60(12):5219-23
references.pmid: 1452354
references.citation: Peptides. 2004 Sep;25(9):1389-403
references.pmid: 15374643
references.citation: J Biol Chem. 1990 Feb 25;265(6):3161-7
references.pmid: 2406246
references.citation: Infect Immun. 1997 Jun;65(6):2119-26
references.pmid: 9169741
references.citation: Clin Microbiol Rev. 2000 Jul;13(3):470-511
references.pmid: 10885988
references.citation: Infect Immun. 2003 Jul;71(7):3857-65
references.pmid: 12819070
references.citation: Inflamm Res. 2008 Mar;57(3):93-6
references.pmid: 18213448
references.citation: J Clin Invest. 1994 Sep;94(3):965-77
references.pmid: 8083381
references.citation: J Exp Med. 2005 Jun 6;201(11):1815-23
references.pmid: 15928201
references.citation: Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6172-6
references.pmid: 1385871
references.citation: Infect Immun. 2000 Jul;68(7):4245-54
references.pmid: 10858242
references.citation: J Biol Chem. 2005 Nov 25;280(47):38948-56
references.pmid: 16174772
references.citation: Microb Pathog. 2006 May;40(5):221-7
references.pmid: 16542816
references.citation: J Exp Med. 1986 Nov 1;164(5):1641-51
references.pmid: 3534131
references.citation: Blood. 2000 Jul 15;96(2):719-26
references.pmid: 10887140
references.citation: J Bacteriol. 1967 Jun;93(6):2024-5
references.pmid: 6025314
references.citation: Lancet Infect Dis. 2005 Nov;5(11):685-94
references.pmid: 16253886
references.citation: Curr Opin Microbiol. 2003 Feb;6(1):77-81
references.pmid: 12615224
references.citation: Infect Immun. 2002 Apr;70(4):2166-70
references.pmid: 11895983