title: cPLA2 regulates the expression of type I interferons and intracellular immunity to Chlamydia trachomatis.
abstract: Infection with the obligate bacterial intracellular pathogen Chlamydia trachomatis leads to the sustained activation of the small GTPase RAS and many of its downstream signaling components. In particular, the mitogen-activated protein kinase ERK and the calcium-dependent phospholipase cPLA(2) are activated and are important for the onset of inflammatory responses. In this study we tested if activation of ERK and cPLA(2) occurred as a result of RAS signaling during infection and determined the relative contribution of these signaling components to chlamydial replication and survival. We provide genetic and pharmacological evidence that during infection RAS, ERK, and, to a lesser extent, cPLA(2) activation are uncoupled, suggesting that Chlamydia activates individual components of this signaling pathway in a non-canonical manner. In human cell lines, inhibition of ERK or cPLA(2) signaling did not adversely impact C. trachomatis replication. In contrast, in murine cells, inhibition of ERK and cPLA(2) played a significant protective role against C. trachomatis. We determined that cPLA(2)-deficient murine cells are permissive for C. trachomatis replication because of their impaired expression of beta interferon and the induction of immunity-related GTPases (IRG) important for the containment of intracellular pathogens. Furthermore, the MAPK p38 was primarily responsible for cPLA(2) activation in Chlamydia-infected cells and IRG expression. Overall, these findings define a previously unrecognized role for cPLA(2) in the induction of cell autonomous cellular immunity to Chlamydia and highlight the many non-canonical signaling pathways engaged during infection.
authors.affiliation: Departments of Molecular Genetics and Microbiology, Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Vignola
authors.forename: David F
authors.initials: DF
authors.lastname: Kashatus
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Taylor
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Counter
authors.forename: Raphael H
authors.initials: RH
authors.lastname: Valdivia
mesh_terms: D000818:Animals; D002460:Cell Line; D002689:Chlamydia / Q000276:immunology* / Q000378:metabolism*; D002692:Chlamydia trachomatis / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D054467:Phospholipases A2 / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D054467:Phospholipases A2; D018631:ras Proteins
references.citation: J Biol Chem. 2004 Mar 5;279(10):9409-16
references.pmid: 14676189
references.citation: Infect Immun. 1996 Oct;64(10):3951-6
references.pmid: 8926054
references.citation: J Biol Chem. 2001 May 11;276(19):15609-15
references.pmid: 11278702
references.citation: Nat Rev Mol Cell Biol. 2008 Feb;9(2):162-76
references.pmid: 18216772
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14092-7
references.pmid: 16959883
references.citation: FEMS Microbiol Rev. 2005 Nov;29(5):949-59
references.pmid: 16043254
references.citation: PLoS Biol. 2009 Sep;7(9):e1000194
references.pmid: 19753100
references.citation: PLoS Pathog. 2009 Nov;5(11):e1000664
references.pmid: 19936056
references.citation: Traffic. 2003 Apr;4(4):214-21
references.pmid: 12694560
references.citation: J Immunol. 2005 Jul 1;175(1):450-60
references.pmid: 15972679
references.citation: Nat Rev Cancer. 2003 Jan;3(1):11-22
references.pmid: 12509763
references.citation: Science. 2003 Aug 1;301(5633):640-3
references.pmid: 12855817
references.citation: Int J Syst Evol Microbiol. 2001 Jan;51(Pt 1):249
references.pmid: 11211265
references.citation: Biochim Biophys Acta. 2002 Mar 14;1602(1):23-45
references.pmid: 11960693
references.citation: J Exp Med. 2001 Jul 16;194(2):181-8
references.pmid: 11457893
references.citation: J Immunol. 2010 Mar 1;184(5):2551-60
references.pmid: 20107183
references.citation: PLoS One. 2009;4(2):e4588
references.pmid: 19242543
references.citation: Infect Immun. 2008 Jul;76(7):3150-5
references.pmid: 18426885
references.citation: Annu Rev Immunol. 2006;24:771-800
references.pmid: 16551266
references.citation: Oncogene. 2008 Apr 24;27(19):2754-62
references.pmid: 17998936
references.citation: Methods Enzymol. 2006;407:128-43
references.pmid: 16757320
references.citation: Nature. 1997 Dec 11;390(6660):622-5
references.pmid: 9403693
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15535-9
references.pmid: 17030789
references.citation: Microbes Infect. 2007 Nov-Dec;9(14-15):1644-51
references.pmid: 18023232
references.citation: Infect Immun. 1998 Dec;66(12):6017-21
references.pmid: 9826388
references.citation: J Biol Chem. 1992 Sep 25;267(27):19448-54
references.pmid: 1527065
references.citation: Infect Immun. 2005 Jul;73(7):4017-24
references.pmid: 15972489
references.citation: Infect Immun. 1981 Mar;31(3):1161-76
references.pmid: 7228399
references.citation: Clin Microbiol Rev. 2009 Apr;22(2):240-73, Table of Contents
references.pmid: 19366914
references.citation: Oncogene. 1997 Feb 6;14(5):623-5
references.pmid: 9053862
references.citation: PLoS Pathog. 2009 Feb;5(2):e1000288
references.pmid: 19197351
references.citation: J Virol. 1998 Nov;72(11):8463-71
references.pmid: 9765382
references.citation: J Immunol. 2008 May 1;180(9):6237-45
references.pmid: 18424746
references.citation: J Biol Chem. 1996 Aug 23;271(34):20399-405
references.pmid: 8702776
references.citation: Trends Microbiol. 2003 Jan;11(1):44-51
references.pmid: 12526854
references.citation: Proc Natl Acad Sci U S A. 2003 May 27;100(11):6771-6
references.pmid: 12743366
references.citation: J Biol Chem. 1999 Jun 11;274(24):17164-70
references.pmid: 10358073
references.citation: PLoS Pathog. 2006 May;2(5):e45
references.pmid: 16710454
references.citation: J Bacteriol. 1997 Dec;179(23):7233-42
references.pmid: 9393685
references.citation: Prog Lipid Res. 2006 Nov;45(6):487-510
references.pmid: 16814865
references.citation: Sci Signal. 2010 Mar 16;3(113):ra21
references.pmid: 20234004
references.citation: Immunobiology. 2007;212(9-10):771-84
references.pmid: 18086378
references.citation: Infect Immun. 2003 Oct;71(10):5855-70
references.pmid: 14500507
references.citation: Mol Cell Biol. 1994 Feb;14(2):1113-21
references.pmid: 8289792
references.citation: Oncogene. 2007 May 14;26(22):3291-310
references.pmid: 17496923
references.citation: J Exp Med. 2003 Oct 6;198(7):1043-55
references.pmid: 14517278
references.citation: Infect Immun. 2007 Dec;75(12):5924-9
references.pmid: 17893134
references.citation: Nat Immunol. 2009 Nov;10(11):1200-7
references.pmid: 19801985
references.citation: Infect Immun. 2004 Nov;72(11):6615-21
references.pmid: 15501794
references.citation: J Biol Chem. 2003 Aug 1;278(31):29336-43
references.pmid: 12732635
references.citation: PLoS One. 2008 Sep 01;3(9):e3102
references.pmid: 18769617
references.citation: Annu Rev Immunol. 2005;23:307-36
references.pmid: 15771573
references.citation: Methods Mol Biol. 2008;445:407-15
references.pmid: 18425465
references.citation: Methods Enzymol. 2006;407:637-47
references.pmid: 16757358
references.citation: Curr Opin Microbiol. 2008 Feb;11(1):53-9
references.pmid: 18299248
references.citation: Infect Immun. 2007 Mar;75(3):1280-90
references.pmid: 17178782
references.citation: Immunobiology. 2008;213(3-4):367-75
references.pmid: 18406381
references.citation: J Exp Med. 2009 Aug 31;206(9):1899-911
references.pmid: 19652017
references.citation: Cell Host Microbe. 2008 Aug 14;4(2):159-69
references.pmid: 18692775
references.citation: Infect Immun. 2006 Sep;74(9):5362-73
references.pmid: 16926431
references.citation: PLoS Pathog. 2005 Nov;1(3):e24
references.pmid: 16304607
references.citation: Infect Immun. 2002 Dec;70(12):6933-9
references.pmid: 12438372
references.citation: PLoS Pathog. 2009 Nov;5(11):e1000665
references.pmid: 19936053
references.citation: Nat Rev Cancer. 2007 Apr;7(4):295-308
references.pmid: 17384584
references.citation: J Immunol. 2005 Jun 1;174(11):7186-93
references.pmid: 15905563
references.citation: Nucleic Acids Res. 1990 Jun 25;18(12):3587-96
references.pmid: 2194165
references.citation: Nature. 2009 Feb 5;457(7230):731-5
references.pmid: 19060882
references.citation: Infect Immun. 2004 Jul;72(7):3951-60
references.pmid: 15213139
references.citation: Infect Immun. 2008 Mar;76(3):942-51
references.pmid: 18086816
references.citation: Curr Opin Microbiol. 2010 Feb;13(1):4-10
references.pmid: 20006538
references.citation: Curr Opin Microbiol. 2009 Feb;12(1):81-7
references.pmid: 19138553
references.citation: J Bacteriol. 1988 Mar;170(3):1389-92
references.pmid: 3343223