title: Early B-cell activation after West Nile virus infection requires alpha/beta interferon but not antigen receptor signaling.
abstract: The B-cell response against West Nile virus (WNV), an encephalitic Flavivirus of global concern, is critical to controlling central nervous system dissemination and neurological sequelae, including death. Here, using a well-characterized mouse model of WNV infection, we examine the factors that govern early B-cell activation. Subcutaneous inoculation with a low dose of replicating WNV results in extensive B-cell activation in the draining lymph node (LN) within days of infection as judged by upregulation of the surface markers CD69, class II major histocompatibility complex, and CD86 on CD19(+) cells. B-cell activation in the LN but not the spleen was dependent on signals through the type I alpha/beta interferon (IFN-alpha/beta) receptor. Despite significant activation in the draining LN at day 3 after infection, WNV-specific B cells were not detected by immunoglobulin M enzyme-linked immunospot analysis until day 7. Liposome depletion experiments demonstrate that B-cell activation after WNV infection was not affected by the loss of F4/80(+) or CD169(+) subcapsular macrophages. Nonetheless, LN myeloid cells were essential for control of viral replication and survival from infection. Overall, our data suggest that the massive, early polyclonal B-cell activation occurring in the draining LN after WNV infection is immunoglobulin receptor and macrophage independent but requires sustained signals through the type I IFN-alpha/beta receptor.
authors.affiliation: Departments of Medicine, Molecular Microbiology and Pathology & Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, MO 63110, USA.
authors.forename: Whitney E
authors.initials: WE
authors.lastname: Purtha
authors.forename: Karen A
authors.initials: KA
authors.lastname: Chachu
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D051940:B7-2 Antigen / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D016898:Interferon-alpha / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology*; D037181:Lectins, C-Type; D047589:Leukocyte Reduction Procedures; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011946:Receptors, Antigen / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D015854:Up-Regulation; D014901:West Nile Fever / Q000276:immunology*; D014902:West Nile virus / Q000276:immunology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051940:B7-2 Antigen; D000949:Histocompatibility Antigens Class II; D016898:Interferon-alpha; D016899:Interferon-beta; D037181:Lectins, C-Type; D011946:Receptors, Antigen; D000099192:CD69 Antigens
references.citation: Virology. 2006 Mar 1;346(1):53-65
references.pmid: 16325883
references.citation: J Virol. 2005 Jun;79(12):7466-77
references.pmid: 15919902
references.citation: Immunity. 2007 Jul;27(1):160-71
references.pmid: 17658276
references.citation: Arch Virol. 1996;141(3-4):459-69
references.pmid: 8645088
references.citation: Science. 2006 Jun 16;312(5780):1672-6
references.pmid: 16778060
references.citation: Eur J Immunol. 2006 Aug;36(8):2094-105
references.pmid: 16810635
references.citation: Curr Opin Neurol. 2006 Aug;19(4):350-7
references.pmid: 16914972
references.citation: PLoS Pathog. 2006 Jun;2(6):e58
references.pmid: 16789842
references.citation: J Virol. 2007 Sep;81(18):9801-11
references.pmid: 17626103
references.citation: Science. 1999 Dec 10;286(5447):2156-9
references.pmid: 10591647
references.citation: J Immunol. 2005 Oct 1;175(7):4635-40
references.pmid: 16177109
references.citation: J Interferon Cytokine Res. 2006 Nov;26(11):804-19
references.pmid: 17115899
references.citation: J Invest Dermatol. 2001 Sep;117(3):702-9
references.pmid: 11564180
references.citation: J Virol. 1999 Feb;73(2):1075-9
references.pmid: 9882308
references.citation: Nature. 2007 Nov 1;450(7166):110-4
references.pmid: 17934446
references.citation: J Virol. 2006 Jun;80(11):5338-48
references.pmid: 16699014
references.citation: PLoS Biol. 2004 Dec;2(12):e432
references.pmid: 15562321
references.citation: J Immunol. 1984 Oct;133(4):1710-5
references.pmid: 6206131
references.citation: Immunity. 2004 Sep;21(3):341-7
references.pmid: 15357945
references.citation: J Exp Med. 1999 Jul 5;190(1):75-89
references.pmid: 10429672
references.citation: J Virol. 2004 Jul;78(13):6974-81
references.pmid: 15194774
references.citation: Nature. 1994 Mar 24;368(6469):339-42
references.pmid: 8127368
references.citation: J Immunol. 2002 Jun 1;168(11):5716-21
references.pmid: 12023371
references.citation: J Immunol. 2007 Feb 1;178(3):1457-67
references.pmid: 17237394
references.citation: J Virol. 2006 Oct;80(19):9424-34
references.pmid: 16973548
references.citation: J Exp Med. 2003 Dec 15;198(12):1853-62
references.pmid: 14662909
references.citation: J Virol. 2006 Dec;80(24):12060-9
references.pmid: 17035323
references.citation: Science. 2002 Dec 13;298(5601):2199-202
references.pmid: 12481138
references.citation: Immunity. 2007 Apr;26(4):491-502
references.pmid: 17379546
references.citation: Nat Immunol. 2007 Sep;8(9):992-1000
references.pmid: 17660822
references.citation: Nature. 2001 Oct 18;413(6857):732-8
references.pmid: 11607032
references.citation: Nature. 2006 Mar 23;440(7083):540-4
references.pmid: 16525420
references.citation: Immunopharmacology. 1999 May;42(1-3):135-49
references.pmid: 10408374
references.citation: Cell. 1992 Mar 6;68(5):869-77
references.pmid: 1547488
references.citation: PLoS Pathog. 2007 Jul 27;3(7):e106
references.pmid: 17676997
references.citation: J Virol. 2005 Nov;79(21):13350-61
references.pmid: 16227257
references.citation: J Immunol Methods. 1992 Aug 30;153(1-2):107-13
references.pmid: 1517581
references.citation: Emerg Infect Dis. 2001 Jul-Aug;7(4):650-3
references.pmid: 11585527
references.citation: J Leukoc Biol. 1990 Mar;47(3):251-7
references.pmid: 2137849
references.citation: Immunol Rev. 2004 Feb;197:192-205
references.pmid: 14962196
references.citation: J Virol. 1995 Mar;69(3):1895-902
references.pmid: 7853531
references.citation: Immunity. 1998 Jul;9(1):143-50
references.pmid: 9697844
references.citation: J Exp Med. 1993 Aug 1;178(2):537-47
references.pmid: 8340758
references.citation: Immunity. 2000 Oct;13(4):539-48
references.pmid: 11070172
references.citation: J Immunol. 2006 Apr 1;176(7):4343-51
references.pmid: 16547272
references.citation: J Immunol Methods. 1994 Sep 14;174(1-2):83-93
references.pmid: 8083541
references.citation: J Virol. 2006 Oct;80(19):9349-60
references.pmid: 16973541
references.citation: J Virol. 2007 Nov;81(21):11828-39
references.pmid: 17715236
references.citation: Cell Immunol. 2006 Feb;239(2):92-102
references.pmid: 16797504
references.citation: Annu Rev Immunol. 2001;19:595-621
references.pmid: 11244048
references.citation: J Virol. 2003 Feb;77(4):2578-86
references.pmid: 12551996
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10338-43
references.pmid: 10468609
references.citation: Nature. 2005 Apr 7;434(7034):772-7
references.pmid: 15800576
references.citation: Immunity. 2001 Apr;14(4):461-70
references.pmid: 11336691
references.citation: Science. 1993 Mar 19;259(5102):1739-42
references.pmid: 8456300