title: Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus.
abstract: The innate immune system limits viral replication via type I interferon and also induces the presentation of viral antigens to cells of the adaptive immune response. Using infection of mice with vesicular stomatitis virus, we analyzed how the innate immune system inhibits viral propagation but still allows the presentation of antigen to cells of the adaptive immune response. We found that expression of the gene encoding the inhibitory protein Usp18 in metallophilic macrophages led to lower type I interferon responsiveness, thereby allowing locally restricted replication of virus. This was essential for the induction of adaptive antiviral immune responses and, therefore, for preventing the fatal outcome of infection. In conclusion, we found that enforced viral replication in marginal zone macrophages was an immunological mechanism that ensured the production of sufficient antigen for effective activation of the adaptive immune response.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Honke
authors.forename: Namir
authors.initials: N
authors.lastname: Shaabani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cadeddu
authors.forename: Ursula R
authors.initials: UR
authors.lastname: Sorg
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Mirko
authors.initials: M
authors.lastname: Trilling
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.forename: Martina
authors.initials: M
authors.lastname: Sauter
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kandolf
authors.forename: Nicole
authors.initials: N
authors.lastname: Gailus
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Christoph
authors.initials: C
authors.lastname: Burkart
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Baldus
authors.forename: Melanie
authors.initials: M
authors.lastname: Grusdat
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hengel
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Masato
authors.initials: M
authors.lastname: Tanaka
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D002461:Cell Line, Transformed; D006224:Cricetinae; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D010450:Endopeptidases / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000378:metabolism; D018353:Rhabdoviridae Infections / Q000276:immunology*; D063267:Sialic Acid Binding Ig-like Lectin 1; D043222:Ubiquitin Thiolesterase; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D053259:Lymphotoxin beta Receptor; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; D010450:Endopeptidases; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase
references.citation: Nature. 2007 Nov 1;450(7166):110-4
references.pmid: 17934446
references.citation: Immunity. 2003 Feb;18(2):255-64
references.pmid: 12594952
references.citation: Immunol Rev. 1997 Apr;156:199-209
references.pmid: 9176709
references.citation: Nat Immunol. 2001 Jun;2(6):487-92
references.pmid: 11376334
references.citation: Semin Immunol. 2000 Jun;12(3):163-71; discussion 257-344
references.pmid: 10910735
references.citation: Immunity. 1998 Jan;8(1):89-95
references.pmid: 9462514
references.citation: N Engl J Med. 1971 Dec 9;285(24):1333-9
references.pmid: 4107718
references.citation: Nat Rev Immunol. 2008 Oct;8(10):764-75
references.pmid: 18825130
references.citation: Adv Anat Embryol Cell Biol. 2000;151:III-IX, 1-101
references.pmid: 10592524
references.citation: Immunol Lett. 2006 Jul 15;106(1):96-8
references.pmid: 16716409
references.citation: Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):314-8
references.pmid: 1309611
references.citation: Eur J Immunol. 1997 Oct;27(10):2626-33
references.pmid: 9368619
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15623-8
references.pmid: 9861020
references.citation: Eur J Immunol. 2006 Aug;36(8):2061-75
references.pmid: 16841297
references.citation: Eur J Immunol. 1994 Feb;24(2):429-34
references.pmid: 8299692
references.citation: Nat Rev Immunol. 2008 Jul;8(7):559-68
references.pmid: 18575461
references.citation: Nat Med. 2004 Dec;10(12):1374-8
references.pmid: 15531891
references.citation: J Virol. 2005 Apr;79(7):4460-9
references.pmid: 15767446
references.citation: J Immunol. 2003 Aug 1;171(3):1148-55
references.pmid: 12874200
references.citation: Immunol Rev. 1997 Apr;156:11-24
references.pmid: 9176696
references.citation: J Clin Invest. 2007 Aug;117(8):2268-78
references.pmid: 17657313
references.citation: Eur J Immunol. 1989 Apr;19(4):675-80
references.pmid: 2471648
references.citation: Liver. 1987 Apr;7(2):63-75
references.pmid: 3302581
references.citation: Eur J Immunol. 1996 Sep;26(9):2257-62
references.pmid: 8814275
references.citation: J Exp Med. 1995 Jul 1;182(1):261-6
references.pmid: 7540654
references.citation: Immunity. 2005 Jan;22(1):19-29
references.pmid: 15664156
references.citation: Cell. 2010 Aug 20;142(4):613-24
references.pmid: 20723761
references.citation: J Immunol. 1993 Jun 1;150(11):5185-94
references.pmid: 8496610
references.citation: Nat Immunol. 2008 Mar;9(3):282-91
references.pmid: 18204450
references.citation: Nature. 2002 Oct 24;419(6909):845-9
references.pmid: 12397360
references.citation: J Exp Med. 1992 Aug 1;176(2):519-29
references.pmid: 1386874
references.citation: Nat Med. 2005 Feb;11(2):138-45
references.pmid: 15654326
references.citation: J Immunol. 2009 Jan 15;182(2):1099-106
references.pmid: 19124753
references.citation: Med Microbiol Immunol. 1994 May;183(2):95-104
references.pmid: 7935164
references.citation: Hepatology. 2010 Jul;52(1):25-32
references.pmid: 20578253
references.citation: N Engl J Med. 1968 Oct 24;279(17):893-900
references.pmid: 20617594
references.citation: Eur J Immunol. 1995 May;25(5):1410-6
references.pmid: 7539759
references.citation: Eur J Immunol. 2006 Aug;36(8):2094-105
references.pmid: 16810635
references.citation: Nat Rev Immunol. 2005 May;5(5):375-86
references.pmid: 15864272
references.citation: Nat Med. 2003 Dec;9(12):1469-76
references.pmid: 14625545
references.citation: Nature. 2010 Jun 24;465(7301):1079-83
references.pmid: 20577213
references.citation: Immunol Rev. 2008 Jun;223:186-201
references.pmid: 18613837
references.citation: Science. 1994 Jun 24;264(5167):1918-21
references.pmid: 8009221
references.citation: J Exp Med. 2009 Jul 6;206(7):1589-602
references.pmid: 19564349
references.citation: Nat Immunol. 2003 Oct;4(10):1009-15
references.pmid: 14502286
references.citation: Virology. 1995 May 10;209(1):257-62
references.pmid: 7747478
references.citation: EMBO J. 2006 Jun 7;25(11):2358-67
references.pmid: 16710296
references.citation: Cell Immunol. 1996 Jan 10;167(1):115-21
references.pmid: 8548834
references.citation: Clin Rev Allergy Immunol. 2005 Jun;28(3):205-20
references.pmid: 16129905
references.citation: J Virol. 1993 Jul;67(7):3917-22
references.pmid: 8389912
references.citation: J Exp Med. 2005 Sep 5;202(5):637-50
references.pmid: 16129706