title: Uncoupling of pro- and anti-inflammatory properties of Staphylococcus aureus.
abstract: Staphylococcus aureus is a Gram-positive bacterium that is carried by a quarter of the healthy human population and that can cause severe infections. This pathobiosis has been linked to a balance between Toll-like receptor 2 (TLR2)-dependent pro- and anti-inflammatory responses. The relationship between these two types of responses is unknown. Analysis of 16 nasal isolates of S. aureus showed heterogeneity in their capacity to induce pro- and anti-inflammatory responses, suggesting that these two responses are independent of each other. Uncoupling of these responses was corroborated by selective signaling through phosphoinositol 3-kinase (PI3K)-Akt-mTOR and extracellular signal-regulated kinase (ERK) for the anti-inflammatory response and through p38 for the proinflammatory response. Uncoupling was also observed at the level of phagocytosis and phagosomal processing of S. aureus, which were required solely for the proinflammatory response. Importantly, the anti-inflammatory properties of an S. aureus isolate correlated with its ability to modulate T cell immunity. Our results suggest the presence of anti-inflammatory TLR2 ligands in the staphylococcal cell wall, whose identification may provide templates for novel immunomodulatory drugs.
authors: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada.
authors: Adam G
authors: AG
authors: Peres
authors: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada.
authors: Camille
authors: C
authors: Stegen
authors: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada.
authors: Junbin
authors: J
authors: Li
authors: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada.
authors: An Qi
authors: AQ
authors: Xu
authors: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada.
authors: Benoit
authors: B
authors: Levast
authors: Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors: Michael G
authors: MG
authors: Surette
authors: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada.
authors: Benoit
authors: B
authors: Cousineau
authors: Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada Centre hospitalier de l'Université de Montréal, Montréal, QC, Canada.
authors: Martin
authors: M
authors: Desrosiers
authors: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada Microbiome and Disease Tolerance Centre, McGill University, Montréal, QC, Canada joaquin.madrenas@mcgill.ca.
authors: Joaquín
authors: J
authors: Madrenas
mesh_terms: D002473:Cell Wall / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology*; D016753:Interleukin-10 / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology* / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C508609:IL10 protein, human; C495342:TLR2 protein, human; C546842:MTOR protein, human
references: Annu Rev Immunol. 2013;31:317-43
references: 23298208
references: Immunity. 2008 Oct 17;29(4):565-77
references: 18848473
references: Nat Med. 2009 Jun;15(6):641-8
references: 19465927
references: Immunity. 2014 Nov 20;41(5):762-75
references: 25456159
references: Clin Microbiol Rev. 2005 Jul;18(3):521-40
references: 16020688
references: J Immunol. 1999 Feb 15;162(4):2016-23
references: 9973473
references: J Immunol. 2010 Jun 15;184(12):7071-81
references: 20483752
references: Nat Immunol. 2012 Nov;13(11):1045-54
references: 23023391
references: J Immunol. 2013 Feb 15;190(4):1591-602
references: 23325892
references: J Infect Dis. 2009 Jun 15;199(12):1820-6
references: 19419332
references: Nat Rev Immunol. 2010 Mar;10(3):170-81
references: 20154735
references: Immunity. 2011 May 27;34(5):637-50
references: 21616434
references: Int J Med Microbiol. 2011 Aug;301(6):500-5
references: 21570348
references: Medicine (Baltimore). 2010 Nov;89(6):403-25
references: 21057262
references: FEMS Microbiol Lett. 2004 Apr 1;233(1):45-52
references: 15043868
references: Cell. 2010 Mar 19;140(6):805-20
references: 20303872
references: Cell Host Microbe. 2008 Oct 16;4(4):350-61
references: 18854239
references: EMBO J. 2009 Jul 22;28(14):2018-27
references: 19574958
references: Int J Biochem Cell Biol. 2010 Jul;42(7):1066-71
references: 20363358
references: Ann Clin Microbiol Antimicrob. 2006;5:2
references: 16469106
references: Front Immunol. 2014 Jan 08;4:507
references: 24409186
references: Eur J Immunol. 2014 May;44(5):1285-98
references: 24470136
references: JAMA Intern Med. 2013 Nov 25;173(21):1970-8
references: 24043270
references: J Immunol. 1994 Jul 15;153(2):811-6
references: 8021515
references: J Infect Dis. 2012 Nov 15;206(10):1604-11
references: 22966128
references: Eur J Immunol. 2013 Jun;43(6):1630-42
references: 23519847
references: Science. 2011 May 20;332(6032):974-7
references: 21512004
references: Emerg Infect Dis. 2007 Dec;13(12):1840-6
references: 18258033
references: Science. 2008 Aug 1;321(5889):691-6
references: 18669862
references: J Immunol. 2013 Feb 15;190(4):1519-27
references: 23315073
references: Science. 2012 Feb 24;335(6071):936-41
references: 22363001
references: Eur J Clin Microbiol Infect Dis. 2012 Oct;31(10):2809-15
references: 22639172
references: Epidemiol Infect. 1995 Aug;115(1):51-60
references: 7641838
references: Nat Med. 2013 Jun;19(6):713-21
references: 23708291
references: FEMS Microbiol Rev. 2008 Jan;32(1):23-37
references: 17983441
references: J Infect Dis. 1984 Mar;149(3):471
references: 6715902
references: Sci Rep. 2012;2:606
references: 22930672
references: Burns. 2013 May;39(3):380-8
references: 23313242
references: Expert Opin Pharmacother. 2004 Aug;5(8):1701-10
references: 15264985
references: BMC Infect Dis. 2014;14:128
references: 24597648
references: J Immunol. 2009 Sep 15;183(6):3642-51
references: 19717524
references: J Cell Biol. 2005 Aug 1;170(3):477-85
references: 16061696
references: BMC Res Notes. 2014;7:428
references: 24996783
references: Emerg Infect Dis. 2005 Jun;11(6):868-72
references: 15963281
references: Nat Med. 2009 Dec;15(12):1377-82
references: 19966777
references: Nat Rev Immunol. 2013 Sep;13(9):679-92
references: 23954936
references: J Exp Med. 2012 Jul 30;209(8):1437-44
references: 22778390
references: J Infect Dis. 2011 Jul 15;204(2):253-62
references: 21673036
references: Nature. 2012 Apr 26;484(7395):514-8
references: 22466287
references: PLoS One. 2014;9(5):e96416
references: 24810614
references: J Clin Microbiol. 2000 Mar;38(3):1008-15
references: 10698988
references: J Immunol. 2011 Dec 1;187(11):6002-10
references: 22031762
references: Lancet. 2004 Aug 21-27;364(9435):703-5
references: 15325835