title: Melanoma differentiation-associated gene 5 is critical for protection against Theiler's virus-induced demyelinating disease.
abstract: Infection of dendritic and glial cells with Theiler's murine encephalomyelitis virus (TMEV) induces various cytokines via Toll-like receptor- and melanoma differentiation-associated gene 5 (MDA5)-dependent pathways. However, the involvement and role of MDA5 in cytokine gene activation and the pathogenesis of TMEV-induced demyelinating disease are largely unknown. In this study, we demonstrate that MDA5 plays a critical role in the production of TMEV-induced alpha interferon (IFN-α) during early viral infection and in protection against the development of virus-induced demyelinating disease. Our results indicate that MDA5-deficient 129SvJ mice display significantly higher viral loads and apparent demyelinating lesions in the central nerve system (CNS) accompanied by clinical symptoms compared with wild-type 129SvJ mice. During acute viral infection, MDA5-deficient mice produced elevated levels of chemokines, consistent with increased cellular infiltration, but reduced levels of IFN-α, known to control T cell responses and cellular infiltration. Additional studies with isolated CNS glial cells from these mice suggest that cells from MDA5-deficient mice are severely compromised in the production of IFN-α upon viral infection, which results in increased cellular infiltration and viral loads in the CNS. Despite inadequate stimulation, the overall T cell responses to the viral determinants were significantly elevated in MDA5-deficient mice, reflecting the increased cellular infiltration. Therefore, the lack of MDA5-mediated IFN-α production may facilitate a massive viral load and elevated cellular infiltration in the CNS during early viral infection, leading to the pathogenesis of demyelinating disease.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois, USA.
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Jin
authors.forename: Seung Jae
authors.initials: SJ
authors.lastname: Kim
authors.forename: Eui Young
authors.initials: EY
authors.lastname: So
authors.forename: Liping
authors.initials: L
authors.lastname: Meng
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Byung S
authors.initials: BS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001483:Base Sequence; D018188:Cardiovirus Infections / Q000517:prevention & control* / Q000821:virology; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D017931:DNA Primers; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017945:Theilovirus / Q000235:genetics / Q000302:isolation & purification*
chemical_list: D017931:DNA Primers; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
references.citation: Nat Rev Immunol. 2006 Sep;6(9):644-58
references.pmid: 16932750
references.citation: J Virol. 2010 Jan;84(1):254-60
references.pmid: 19846534
references.citation: J Immunol. 2005 Sep 1;175(5):2851-8
references.pmid: 16116171
references.citation: J Neurochem. 2009 Mar;108(6):1343-59
references.pmid: 19154336
references.citation: Curr Opin Immunol. 2011 Feb;23(1):57-64
references.pmid: 21123041
references.citation: J Immunol. 1995 Nov 1;155(9):4497-503
references.pmid: 7594613
references.citation: PLoS Pathog. 2008 Jul 18;4(7):e1000108
references.pmid: 18636103
references.citation: Nat Immunol. 2005 Oct;6(10):981-8
references.pmid: 16127453
references.citation: J Virol. 1986 Dec;60(3):1163-5
references.pmid: 3023668
references.citation: J Biol Chem. 2007 May 25;282(21):15325-9
references.pmid: 17395583
references.citation: J Exp Med. 2006 Jul 10;203(7):1795-803
references.pmid: 16785313
references.citation: Immunol Res. 2005;31(1):1-12
references.pmid: 15591618
references.citation: Mult Scler. 1995 Jun;1(2):95-103
references.pmid: 9345459
references.citation: Ann Neurol. 1995 May;37(5):611-9
references.pmid: 7755356
references.citation: Immunology. 2011 Apr;132(4):466-74
references.pmid: 21320124
references.citation: J Virol. 2001 Oct;75(20):9780-9
references.pmid: 11559811
references.citation: J Biochem. 2007 Feb;141(2):137-45
references.pmid: 17190786
references.citation: J Exp Med. 2000 May 15;191(10):1777-88
references.pmid: 10811870
references.citation: J Virol. 2008 Jan;82(1):335-45
references.pmid: 17942531
references.citation: J Neuroimmunol. 2001 Jul 2;117(1-2):166-70
references.pmid: 11431017
references.citation: Glia. 2007 Feb;55(3):239-52
references.pmid: 17091495
references.citation: J Virol. 2006 Mar;80(6):2913-23
references.pmid: 16501100
references.citation: Immunity. 2001 Jun;14(6):661-4
references.pmid: 11420036
references.citation: J Immunol. 1995 May 1;154(9):4309-21
references.pmid: 7722289
references.citation: Immunol Cell Biol. 1998 Feb;76(1):34-40
references.pmid: 9553774
references.citation: Blood. 2002 May 1;99(9):3263-71
references.pmid: 11964292
references.citation: Glia. 2009 Aug 15;57(11):1216-26
references.pmid: 19191335
references.citation: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8459-64
references.pmid: 16714379
references.citation: Glia. 2008 Jul;56(9):942-53
references.pmid: 18383344
references.citation: Glia. 2004 Feb;45(3):287-96
references.pmid: 14730702
references.citation: J Virol. 1987 May;61(5):1507-16
references.pmid: 3033278
references.citation: Vaccine. 2009 Dec 30;27 Suppl 6:G17-20
references.pmid: 20006134
references.citation: J Mol Med (Berl). 2005 Mar;83(3):180-92
references.pmid: 15635478
references.citation: Br J Exp Pathol. 1983 Feb;64(1):57-65
references.pmid: 6301522
references.citation: J Neuroimmunol. 2010 Sep 14;226(1-2):27-37
references.pmid: 20538350
references.citation: Glia. 2006 Jun;53(8):858-67
references.pmid: 16586493
references.citation: Eur J Immunol. 2008 Oct;38(10):2718-26
references.pmid: 18825744
references.citation: J Immunol. 2007 Aug 1;179(3):1438-48
references.pmid: 17641009
references.citation: Oncogene. 2004 Mar 4;23(9):1789-800
references.pmid: 14676839
references.citation: J Virol. 2008 Nov;82(21):10349-58
references.pmid: 18715906
references.citation: PLoS Pathog. 2007 Aug 24;3(8):e124
references.pmid: 17722981
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):637-42
references.pmid: 11805321
references.citation: Nature. 2006 May 4;441(7089):101-5
references.pmid: 16625202
references.citation: J Virol. 2009 Oct;83(20):10761-9
references.pmid: 19656871
references.citation: J Exp Med. 2009 Feb 16;206(2):313-28
references.pmid: 19204109
references.citation: J Virol. 2003 Jun;77(11):6322-31
references.pmid: 12743289
references.citation: Methods. 1996 Dec;10(3):453-61
references.pmid: 8954856