Multiple MyD88-dependent responses contribute to pulmonary clearance of Legionella pneumophila.
MyD88-dependent signalling is important for secretion of early inflammatory cytokines and host protection in response to Legionella pneumophila infection. Although toll-like receptor (TLR)2 contributes to MyD88-dependent clearance of L. pneumophila, TLR-independent functions of MyD88 could also be important. To determine why MyD88 is critical for host protection to L. pneumophila, the contribution of multiple TLRs and IL-18 receptor (IL-18R)-dependent interferon-gamma (IFN-gamma) production in a mouse was examined. Mice deficient for TLR5 or TLR9, or deficient for TLR2 along with either TLR5 or TLR9, were competent for controlling bacterial replication and had no apparent defects in cytokine production compared with control mice. MyD88-dependent production of IFN-gamma in the lung was mediated primarily by natural killer cells and required IL-18R signalling. Reducing IFN-gamma levels did not greatly affect the kinetics of L. pneumophila replication or clearance in infected mice. Additionally, IFN-gamma-deficient mice did not have a susceptibility phenotype as severe as the MyD88-deficient mice and were able to control a pulmonary infection by L. pneumophila. Thus, MyD88-dependent innate immune responses induced by L. pneumophila involve both TLR-dependent responses and IL-18R-dependent production of IFN-gamma by natural killer cells, and these MyD88-dependent pathways can function independently to provide host protection against an intracellular pathogen.
Archer
Kristina A
KA
Section of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA. craig.roy@yale.edu
Alexopoulou
Lena
L
Flavell
Richard A
RA
Roy
Craig R
CR
D000818:Animals; D015169:Colony Count, Microbial; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency; D007694:Killer Cells, Natural / Q000276:immunology; D016952:Legionella pneumophila / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D053724:Receptors, Interleukin-18 / Q000276:immunology; D015398:Signal Transduction; D016019:Survival Analysis; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000172:deficiency / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000276:immunology
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053724:Receptors, Interleukin-18; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma
Science. 2004 Mar 5;303(5663):1522-6
15001781
Nature. 2000 Dec 7;408(6813):740-5
11130078
Annu Rev Immunol. 2002;20:197-216
11861602
Nat Rev Immunol. 2002 May;2(5):336-45
12033739
N Engl J Med. 1977 Dec 1;297(22):1189-97
335244
J Immunol. 2001 Jul 15;167(2):957-65
11441104
Infect Immun. 1998 Jan;66(1):65-9
9423840
Infect Immun. 1995 Sep;63(9):3609-20
7642298
Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1669-74
9465074
J Clin Invest. 1980 Sep;66(3):441-50
7190579
J Biol Chem. 2006 Nov 17;281(46):35217-23
16984919
Antimicrob Agents Chemother. 1989 Dec;33(12):2132-6
2619277
J Exp Med. 2006 Apr 17;203(4):1093-104
16606669
J Immunol. 2007 Mar 1;178(5):2706-13
17312112
Mol Microbiol. 1998 May;28(3):663-74
9632267
Science. 2004 Mar 5;303(5663):1526-9
14976262
Science. 2005 Jun 10;308(5728):1626-9
15860593
J Exp Med. 2003 Nov 17;198(10):1563-72
14623910
J Exp Med. 1983 Oct 1;158(4):1319-31
6619736
J Immunol. 1988 Jun 1;140(11):3978-81
3131422
Infect Immun. 2008 Jul;76(7):2895-904
18426877
J Immunol. 2007 Nov 15;179(10):6981-7
17982089
Science. 1998 Feb 6;279(5352):873-6
9452389
Trends Microbiol. 1996 Jul;4(7):286-90
8829338
Infect Immun. 2005 Jan;73(1):352-61
15618172
J Infect Dis. 2002 Aug 15;186(4):570-3
12195388
J Clin Microbiol. 1979 Oct;10(4):437-41
393713
Infect Immun. 2000 Dec;68(12):6567-73
11083766
PLoS Pathog. 2006 Mar;2(3):e18
16552444
Infect Immun. 2006 Jun;74(6):3325-33
16714560
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):841-6
14715899
J Cell Sci. 2003 Jan 15;116(Pt 2):293-302
12482915
Science. 2004 May 14;304(5673):1014-8
15143282
Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12487-92
16891416
Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9607-11
1409673
Annu Rev Immunol. 1995;13:151-77
7612219
Immunity. 1998 Jul;9(1):143-50
9697844
Nat Cell Biol. 2002 Dec;4(12):945-54
12447391
Infect Immun. 2004 May;72(5):3048-53
15102819
Am J Pathol. 1994 Dec;145(6):1537-46
7992856
N Engl J Med. 1977 Dec 1;297(22):1197-203
335245
Nat Immunol. 2004 Oct;5(10):1061-8
15361868
J Immunol. 2000 Aug 15;165(4):1847-53
10925263
J Immunol. 2006 May 15;176(10):6162-71
16670325
J Immunol. 2005 Dec 15;175(12):8181-90
16339557
J Exp Med. 2005 Dec 19;202(12):1715-24
16365150
J Infect Dis. 1997 Oct;176(4):1019-28
9333161
Science. 2002 Jan 25;295(5555):679-82
11809974
Infect Immun. 1995 Sep;63(9):3253-8
7642253
J Exp Med. 2006 Sep 4;203(9):2177-89
16940169
Infect Immun. 2007 Jan;75(1):146-51
17060467
Immunity. 1999 Oct;11(4):443-51
10549626
Nature. 1997 Jul 24;388(6640):394-7
9237759
J Exp Med. 2004 May 3;199(9):1201-11
15117975
J Immunol. 1986 Oct 15;137(8):2662-9
3093580
Annu Rev Immunol. 2001;19:423-74
11244043
Infect Immun. 1993 Dec;61(12):5361-73
8225610
Nat Immunol. 2006 Mar;7(3):318-25
16444259
Infect Immun. 1997 Sep;65(9):3594-9
9284124
J Infect Dis. 2006 Jun 15;193(12):1693-702
16703513
J Med Microbiol. 2002 Mar;51(3):225-230
11871617