Gut commensal bacteria direct a protective immune response against Toxoplasma gondii.
Toxoplasma gondii is a universally distributed pathogen that infects over one billion people worldwide. Host resistance to this protozoan parasite depends on a Th1 immune response with potent production of the cytokines interleukin-12 and interferon gamma. Although Toll-like receptor 11 (TLR11) plays a major role in controlling Th1 immunity to this pathogen in mice, this innate immune receptor is nonfunctional in humans, and the mechanisms of TLR11-independent sensing of T. gondii remain elusive. Here, we show that oral infection by T. gondii triggers a TLR11-independent but MyD88-dependent Th1 response that is impaired in TLR2xTLR4 double knockout and TLR9 single knockout mice. These mucosal innate and adaptive immune responses to T. gondii rely on the indirect stimulation of dendritic cells by normal gut microflora. Thus, our results reveal that gut commensal bacteria can serve as molecular adjuvants during parasitic infection, providing indirect immunostimulation that protects against T. gondii in the absence of TLR11.
Benson
Alicia
A
Department of Immunology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Pifer
Reed
R
Behrendt
Cassie L
CL
Hooper
Lora V
LV
Yarovinsky
Felix
F
D000818:Animals; D001419:Bacteria / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology* / Q000469:parasitology / Q000473:pathology
D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9
Immunity. 2003 Nov;19(5):641-4
14614851
Infect Immun. 1994 Jul;62(7):2818-24
7911785
Science. 2005 Jun 10;308(5728):1626-9
15860593
Eur J Immunol. 2004 Nov;34(11):3197-207
15368276
Mol Cells. 2005 Oct 31;20(2):288-96
16267405
Annu Rev Immunol. 2007;25:381-418
17378762
J Exp Med. 1997 Dec 1;186(11):1819-29
9382881
Cell Host Microbe. 2008 Feb 14;3(2):77-87
18312842
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9577-82
15976025
Nature. 2008 May 29;453(7195):620-5
18509436
Microbiol Mol Biol Rev. 2000 Sep;64(3):607-23
10974128
Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6115-9
8100999
J Immunol. 2006 Jun 15;176(12):7589-97
16751405
Trends Parasitol. 2004 Dec;20(12):567-74
15522666
J Immunol. 2006 Aug 1;177(3):1618-27
16849470
Nature. 2008 Oct 9;455(7214):804-7
18724361
Infect Immun. 2008 Mar;76(3):907-15
18160481
Science. 2004 Apr 9;304(5668):248-53
15073368
Nat Rev Immunol. 2004 Jun;4(6):478-85
15173836
Ann N Y Acad Sci. 2006 Aug;1072:332-8
17057213
Immunity. 2007 Apr;26(4):461-75
17398123
Nat Immunol. 2007 Oct;8(10):1086-94
17873879
Nat Rev Immunol. 2008 Jun;8(6):411-20
18469830
Nat Immunol. 2004 Nov;5(11):1091-5
15496943
Immunol Rev. 2006 Aug;212:256-71
16903919
Nat Rev Immunol. 2008 Jun;8(6):435-46
18500229
J Immunol. 1996 Jul 15;157(2):798-805
8752931
J Immunol. 1996 Nov 1;157(9):4045-54
8892638
Nat Immunol. 2006 Feb;7(2):117-20
16424884
Science. 2001 Feb 2;291(5505):881-4
11157169
J Immunol. 2006 Dec 15;177(12):8785-95
17142781
Trends Microbiol. 2008 Mar;16(3):107-14
18280160
Immunity. 2006 Sep;25(3):473-85
16949315
Science. 2005 Mar 25;307(5717):1915-20
15790844
J Immunol. 2002 Jun 15;168(12):5997-6001
12055206
J Immunol. 2004 Aug 1;173(3):1887-93
15265921
J Exp Med. 2006 Jul 10;203(7):1805-15
16818672
Int Rev Immunol. 2002 Jul-Oct;21(4-5):373-403
12486820
Immunity. 2006 Oct;25(4):655-64
17000122
Science. 1988 Apr 22;240(4851):516-8
3128869
Science. 2005 Feb 4;307(5710):734-8
15692052
J Exp Med. 1996 Aug 1;184(2):597-607
8760813
Cell. 2004 Jul 23;118(2):229-41
15260992
Int Immunol. 2003 Sep;15(9):1081-7
12917260
Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20858-63
19075245
Immunol Lett. 2008 Aug 15;119(1-2):17-21
18617274
J Immunol. 2004 Jun 1;172(11):6954-60
15153515
J Immunol. 2008 Sep 1;181(5):3464-73
18714019
Science. 2005 Feb 4;307(5710):731-4
15692051
J Immunol. 2007 Jul 15;179(2):1129-37
17617606
J Exp Med. 2008 Feb 18;205(2):451-64
18268035
Science. 2006 Aug 25;313(5790):1126-30
16931762