title: A chemokine-like viral protein enhances alpha interferon production by plasmacytoid dendritic cells but delays CD8+ T cell activation and impairs viral clearance.
abstract: Murine cytomegalovirus encodes numerous proteins that act on a variety of pathways to modulate the innate and adaptive immune responses. Here, we demonstrate that a chemokine-like protein encoded by murine cytomegalovirus activates the early innate immune response and delays adaptive immunity, thereby impairing viral clearance. The protein, m131/129 (also known as MCK-2), is not required to establish infection in the spleen; however, a mutant virus lacking m131/129 was cleared more rapidly from this organ. In the absence of m131/129 expression, there was enhanced activation of dendritic cells (DC), and virus-specific CD8(+) T cells were recruited into the immune response earlier. Viral mutants lacking m131/129 elicited weaker production of alpha interferon (IFN-α) at 40 h postinfection, indicating that this protein exerts its effects during early rounds of viral replication in the spleen. Furthermore, while wild-type and mutant viruses activated plasmacytoid dendritic cells (pDC) equally at this time, as measured by the upregulation of costimulatory molecules, the presence of m131/129 stimulated more pDC to secrete IFN-α, accounting for the stronger IFN-α response than from the wild-type virus. These data provide evidence for a novel immunomodulatory function of a viral chemokine and expose the multifunctionality of immune evasion proteins. In addition, these results broaden our understanding of the interplay between innate and adaptive immunity.
authors: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia.
authors: Matthew E
authors: ME
authors: Wikstrom
authors: Peter
authors: P
authors: Fleming
authors: Iain
authors: I
authors: Comerford
authors: Shaun R
authors: SR
authors: McColl
authors: Christopher E
authors: CE
authors: Andoniou
authors: Mariapia A
authors: MA
authors: Degli-Esposti
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D019742:Chemokines, CC / Q000276:immunology / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057131:Immune Evasion / Q000276:immunology*; D007113:Immunity, Innate / Q000187:drug effects*; D016898:Interferon-alpha / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D018709:Statistics, Nonparametric; D014764:Viral Proteins / Q000276:immunology / Q000494:pharmacology*
chemical_list: D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D016898:Interferon-alpha; C121663:MCK-2 protein, Mouse cytomegalovirus 1; D014764:Viral Proteins
references: J Immunol. 2005 Jun 1;174(11):7217-25
references: 15905567
references: Curr Opin Immunol. 2011 Feb;23(1):96-103
references: 21146386
references: PLoS Pathog. 2007 Aug 24;3(8):e123
references: 17722980
references: J Virol. 1985 May;54(2):422-8
references: 2985805
references: Nat Immunol. 2005 Oct;6(10):1011-9
references: 16142239
references: Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10881-6
references: 10485920
references: Curr Opin Immunol. 2010 Aug;22(4):482-7
references: 20598516
references: J Exp Med. 1998 Aug 3;188(3):577-88
references: 9687534
references: Immunity. 2012 Jul 27;37(1):122-33
references: 22840843
references: J Virol. 1996 Jan;70(1):78-83
references: 8523595
references: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14118-23
references: 18768787
references: Brief Funct Genomic Proteomic. 2005 Nov;4(3):203-13
references: 16420746
references: Int Immunol. 2008 Jan;20(1):45-56
references: 18000008
references: Immunity. 2004 Jul;21(1):107-19
references: 15345224
references: J Virol. 2008 May;82(10):4931-7
references: 18337574
references: Virology. 2006 Sep 1;352(2):450-65
references: 16781754
references: J Virol. 1995 Feb;69(2):904-9
references: 7815559
references: Arch Virol. 1984;81(1-2):139-50
references: 6331345
references: J Exp Med. 2002 Feb 18;195(4):517-28
references: 11854364
references: Nat Immunol. 2001 Oct;2(10):951-6
references: 11550009
references: Blood. 2006 Jan 1;107(1):30-8
references: 16046529
references: Immunity. 2010 Dec 14;33(6):955-66
references: 21130004
references: J Virol. 2008 Jan;82(1):60-70
references: 17942555
references: J Immunol. 2003 Jul 1;171(1):27-31
references: 12816979
references: Science. 2001 May 4;292(5518):934-7
references: 11340207
references: J Virol. 2001 Oct;75(20):9966-76
references: 11559829
references: J Virol. 1999 Aug;73(8):6800-9
references: 10400778
references: J Immunol. 1996 Jun 15;156(12):4746-56
references: 8648121
references: Virol J. 2009 Jan 09;6:4
references: 19134204
references: Science. 2007 Aug 3;317(5838):670-4
references: 17673664
references: J Virol. 2011 Oct;85(19):10346-53
references: 21813614
references: Nat Rev Immunol. 2008 Apr;8(4):259-68
references: 18340344
references: J Virol. 1999 May;73(5):3682-91
references: 10196260
references: Virology. 2008 Sep 15;379(1):45-54
references: 18656220
references: J Interferon Cytokine Res. 1999 Aug;19(8):869-76
references: 10476931
references: J Virol. 2004 Sep;78(18):10023-33
references: 15331735
references: J Leukoc Biol. 2002 Jul;72(1):24-34
references: 12101259
references: J Exp Med. 2003 Apr 7;197(7):885-98
references: 12682109
references: J Exp Med. 1990 May 1;171(5):1469-83
references: 2159050
references: Immunol Cell Biol. 2009 Oct;87(7):559-66
references: 19564888
references: Immunity. 2001 Oct;15(4):617-26
references: 11672543
references: Cell Host Microbe. 2008 Feb 14;3(2):67-76
references: 18312841
references: Immunology. 2000 Feb;99(2):170-8
references: 10692033
references: J Exp Med. 2010 Jun 7;207(6):1333-43
references: 20513749
references: J Immunol. 2002 Oct 15;169(8):4279-87
references: 12370359
references: Virus Genes. 2004 Aug;29(1):43-61
references: 15215683
references: Virol J. 2005 Feb 23;2:14
references: 15727684
references: J Immunol. 2003 Jun 15;170(12):6298-306
references: 12794163
references: J Gen Virol. 2009 Jan;90(Pt 1):33-43
references: 19088270
references: PLoS Pathog. 2006 Mar;2(3):e16
references: 16518465
references: Immunogenetics. 1999 Mar;49(3):238-41
references: 9914339
references: J Immunol. 2005 Nov 15;175(10):6723-32
references: 16272328
references: Nat Rev Immunol. 2008 Dec;8(12):911-22
references: 18989317
references: Nature. 1989 Feb 16;337(6208):651-3
references: 2465495