cPLA2 regulates the expression of type I interferons and intracellular immunity to Chlamydia trachomatis.
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.
Vignola
Mark J
MJ
Departments of Molecular Genetics and Microbiology, Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kashatus
David F
DF
Taylor
Gregory A
GA
Counter
Christopher M
CM
Valdivia
Raphael H
RH
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
D007370:Interferon Type I; D054467:Phospholipases A2; D018631:ras Proteins
J Biol Chem. 2004 Mar 5;279(10):9409-16
14676189
Infect Immun. 1996 Oct;64(10):3951-6
8926054
J Biol Chem. 2001 May 11;276(19):15609-15
11278702
Nat Rev Mol Cell Biol. 2008 Feb;9(2):162-76
18216772
Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14092-7
16959883
FEMS Microbiol Rev. 2005 Nov;29(5):949-59
16043254
PLoS Biol. 2009 Sep;7(9):e1000194
19753100
PLoS Pathog. 2009 Nov;5(11):e1000664
19936056
Traffic. 2003 Apr;4(4):214-21
12694560
J Immunol. 2005 Jul 1;175(1):450-60
15972679
Nat Rev Cancer. 2003 Jan;3(1):11-22
12509763
Science. 2003 Aug 1;301(5633):640-3
12855817
Int J Syst Evol Microbiol. 2001 Jan;51(Pt 1):249
11211265
Biochim Biophys Acta. 2002 Mar 14;1602(1):23-45
11960693
J Exp Med. 2001 Jul 16;194(2):181-8
11457893
J Immunol. 2010 Mar 1;184(5):2551-60
20107183
PLoS One. 2009;4(2):e4588
19242543
Infect Immun. 2008 Jul;76(7):3150-5
18426885
Annu Rev Immunol. 2006;24:771-800
16551266
Oncogene. 2008 Apr 24;27(19):2754-62
17998936
Methods Enzymol. 2006;407:128-43
16757320
Nature. 1997 Dec 11;390(6660):622-5
9403693
Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15535-9
17030789
Microbes Infect. 2007 Nov-Dec;9(14-15):1644-51
18023232
Infect Immun. 1998 Dec;66(12):6017-21
9826388
J Biol Chem. 1992 Sep 25;267(27):19448-54
1527065
Infect Immun. 2005 Jul;73(7):4017-24
15972489
Infect Immun. 1981 Mar;31(3):1161-76
7228399
Clin Microbiol Rev. 2009 Apr;22(2):240-73, Table of Contents
19366914
Oncogene. 1997 Feb 6;14(5):623-5
9053862
PLoS Pathog. 2009 Feb;5(2):e1000288
19197351
J Virol. 1998 Nov;72(11):8463-71
9765382
J Immunol. 2008 May 1;180(9):6237-45
18424746
J Biol Chem. 1996 Aug 23;271(34):20399-405
8702776
Trends Microbiol. 2003 Jan;11(1):44-51
12526854
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6771-6
12743366
J Biol Chem. 1999 Jun 11;274(24):17164-70
10358073
PLoS Pathog. 2006 May;2(5):e45
16710454
J Bacteriol. 1997 Dec;179(23):7233-42
9393685
Prog Lipid Res. 2006 Nov;45(6):487-510
16814865
Sci Signal. 2010 Mar 16;3(113):ra21
20234004
Immunobiology. 2007;212(9-10):771-84
18086378
Infect Immun. 2003 Oct;71(10):5855-70
14500507
Mol Cell Biol. 1994 Feb;14(2):1113-21
8289792
Oncogene. 2007 May 14;26(22):3291-310
17496923
J Exp Med. 2003 Oct 6;198(7):1043-55
14517278
Infect Immun. 2007 Dec;75(12):5924-9
17893134
Nat Immunol. 2009 Nov;10(11):1200-7
19801985
Infect Immun. 2004 Nov;72(11):6615-21
15501794
J Biol Chem. 2003 Aug 1;278(31):29336-43
12732635
PLoS One. 2008 Sep 01;3(9):e3102
18769617
Annu Rev Immunol. 2005;23:307-36
15771573
Methods Mol Biol. 2008;445:407-15
18425465
Methods Enzymol. 2006;407:637-47
16757358
Curr Opin Microbiol. 2008 Feb;11(1):53-9
18299248
Infect Immun. 2007 Mar;75(3):1280-90
17178782
Immunobiology. 2008;213(3-4):367-75
18406381
J Exp Med. 2009 Aug 31;206(9):1899-911
19652017
Cell Host Microbe. 2008 Aug 14;4(2):159-69
18692775
Infect Immun. 2006 Sep;74(9):5362-73
16926431
PLoS Pathog. 2005 Nov;1(3):e24
16304607
Infect Immun. 2002 Dec;70(12):6933-9
12438372
PLoS Pathog. 2009 Nov;5(11):e1000665
19936053
Nat Rev Cancer. 2007 Apr;7(4):295-308
17384584
J Immunol. 2005 Jun 1;174(11):7186-93
15905563
Nucleic Acids Res. 1990 Jun 25;18(12):3587-96
2194165
Nature. 2009 Feb 5;457(7230):731-5
19060882
Infect Immun. 2004 Jul;72(7):3951-60
15213139
Infect Immun. 2008 Mar;76(3):942-51
18086816
Curr Opin Microbiol. 2010 Feb;13(1):4-10
20006538
Curr Opin Microbiol. 2009 Feb;12(1):81-7
19138553
J Bacteriol. 1988 Mar;170(3):1389-92
3343223