MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus.
Infection by RNA viruses is detected by the host through Toll-like receptors or RIG-I-like receptors. Toll-like receptors and RIG-I-like receptors signal through the adaptors MyD88 and MAVS, respectively, to induce type I IFNs (IFN-I) and other antiviral molecules, which are thought to be essential for activating the adaptive immune system. We investigated the role of these adaptors in innate and adaptive immune responses against respiratory syncytial virus (RSV), a common human pathogen. Deletion of Mavs abolished the induction of IFN-I and other proinflammatory cytokines by RSV. Genome-wide expression profiling in the lung showed that the vast majority of RSV-induced genes depended on MAVS. Although Myd88 deficiency did not affect most RSV-induced genes, mice lacking both adaptors harbored a higher and more prolonged viral load and exhibited more severe pulmonary disease than those lacking either adaptor alone. Surprisingly, Myd88(-/-)Mavs(-/-) mice were able to activate a subset of pulmonary dendritic cells that traffic to the draining lymph node in response to RSV. These mice subsequently mounted a normal cytotoxic T-lymphocyte response and demonstrated delayed but effective viral clearance. These results provide an example of a normal and effective adaptive immune response in the absence of innate immunity mediated by MAVS and MyD88.
Bhoj
Vijay G
VG
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Sun
Qinmiao
Q
Bhoj
Elizabeth J
EJ
Somers
Cynthia
C
Chen
Xiang
X
Torres
Juan-Pablo
JP
Mejias
Asuncion
A
Gomez
Ana M
AM
Jafri
Hasan
H
Ramilo
Octavio
O
Chen
Zhijian J
ZJ
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000276:immunology*; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; C512612:MAVS protein, mouse
J Exp Med. 2006 May 15;203(5):1153-9
16682497
Virology. 2005 Jul 5;337(2):335-43
15916793
Proc Am Thorac Soc. 2005;2(2):166-73
16113487
Cell. 2006 Feb 24;124(4):783-801
16497588
Immunity. 2007 Sep;27(3):370-83
17892846
Science. 2006 Nov 10;314(5801):994-7
17038590
J Clin Invest. 1991 Sep;88(3):1026-33
1909350
Cell Res. 2006 Feb;16(2):141-7
16474426
Nat Immunol. 2004 Oct;5(10):971-4
15454919
Nature. 1998 Mar 19;392(6673):245-52
9521319
Immunity. 2005 Jul;23(1):19-28
16039576
Mol Cell. 2005 Sep 16;19(6):727-40
16153868
Proc Am Thorac Soc. 2005;2(2):121-5
16113479
J Immunol. 1999 Apr 1;162(7):4207-11
10201948
Cold Spring Harb Symp Quant Biol. 1999;64:429-35
11232318
Cell. 2005 Sep 9;122(5):669-82
16125763
Pediatr Infect Dis J. 2003 Feb;22(2 Suppl):S13-8; discussion S18-20
12671448
Antivir Ther. 2007;12(4 Pt B):659-70
17944273
Nat Immunol. 2005 Oct;6(10):981-8
16127453
Science. 2006 Nov 10;314(5801):997-1001
17038589
Nature. 2005 Feb 24;433(7028):887-92
15711573
Immunity. 2007 Aug;27(2):240-52
17723216
J Infect Dis. 2004 May 15;189(10):1856-65
15122522
Immunity. 2006 May;24(5):633-42
16713980
J Immunol. 2007 Oct 1;179(7):4711-20
17878370
J Immunol. 2007 May 1;178(9):5820-7
17442966
J Virol. 2007 Sep;81(18):9790-800
17626092
J Virol. 2008 Jan;82(1):196-206
17942529
Nature. 2005 Oct 20;437(7062):1167-72
16177806
J Immunol. 2006 Nov 1;177(9):6263-70
17056556
J Pediatr. 2003 Nov;143(5 Suppl):S112-7
14615709