title: Type I interferon signals in macrophages and dendritic cells control dengue virus infection: implications for a new mouse model to test dengue vaccines.
abstract: Dengue virus (DENV) infects an estimated 400 million people every year, causing prolonged morbidity and sometimes mortality. Development of an effective vaccine has been hampered by the lack of appropriate small animal models; mice are naturally not susceptible to DENV and only become infected if highly immunocompromised. Mouse models lacking both type I and type II interferon (IFN) receptors (AG129 mice) or the type I IFN receptor (IFNAR(-/-) mice) are susceptible to infection with mouse-adapted DENV strains but are severely impaired in mounting functional immune responses to the virus and thus are of limited use for study. Here we used conditional deletion of the type I IFN receptor (IFNAR) on individual immune cell subtypes to generate a minimally manipulated mouse model that is susceptible to DENV while retaining global immune competence. Mice lacking IFNAR expression on CD11c(+) dendritic cells and LysM(+) macrophages succumbed completely to DENV infection, while mice deficient in the receptor on either CD11c(+) or LysM(+) cells were susceptible to infection but often resolved viremia and recovered fully from infection. Conditional IFNAR mice responded with a swift and strong CD8(+) T-cell response to viral infection, compared to a weak response in IFNAR(-/-) mice. Furthermore, mice lacking IFNAR on either CD11c(+) or LysM(+) cells were also sufficiently immunocompetent to raise a protective immune response to a candidate subunit vaccine against DENV-2. These data demonstrate that mice with conditional deficiencies in expression of the IFNAR represent improved models for the study of DENV immunology and screening of vaccine candidates.
  
  
  OBJECTIVE
  Dengue virus infects 400 million people every year worldwide, causing 100 million clinically apparent infections, which can be fatal if untreated. Despite many years of research, there are no effective vaccine and no antiviral treatment available for dengue. Development of vaccines has been hampered in particular by the lack of a suitable small animal model. Mouse models used to test dengue vaccine are deficient in interferon (IFN) type I signaling and severely immunocompromised and therefore likely not ideal for the testing of vaccines. In this study, we explored alternative models lacking the IFN receptor only on certain cell types. We show that mice lacking the IFN receptor on either CD11c- or LysM-expressing cells (conditional IFNAR mice) are susceptible to dengue virus infection. Importantly, we demonstrate that conditional IFN receptor knockout mice generate a better immune response to live virus and a candidate dengue vaccine compared to IFNAR mice and are resistant to subsequent challenge.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore roland_zuest@immunol.a-star.edu.sg.
authors.forename: Roland
authors.initials: R
authors.lastname: Züst
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
authors.forename: Ying-Xiu
authors.initials: YX
authors.lastname: Toh
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.
authors.forename: Iris
authors.initials: I
authors.lastname: Valdés
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cerny
authors.affiliation: Institute for Experimental Infection Research, Twincore, Center for Experimental and Clinical Infection Research, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Heinrich
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.
authors.forename: Lisset
authors.initials: L
authors.lastname: Hermida
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Marcos
authors.affiliation: Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Guillén
authors.affiliation: Institute for Experimental Infection Research, Twincore, Center for Experimental and Clinical Infection Research, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Novartis Institute for Tropical Diseases, Chromos, Singapore Wadsworth Center, New York Department of Health, Albany, New York, USA.
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
authors.forename: Katja
authors.initials: K
authors.lastname: Fink
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D003715:Dengue / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D053059:Dengue Vaccines / Q000627:therapeutic use*; D003716:Dengue Virus / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007114:Immunization; D007370:Interferon Type I / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012367:RNA, Viral / Q000235:genetics; D014779:Virus Replication
chemical_list: D016207:Cytokines; D053059:Dengue Vaccines; D007370:Interferon Type I; D012367:RNA, Viral; D007371:Interferon-gamma
references.citation: J Infect Dis. 2007 Mar 1;195(5):665-74
references.pmid: 17262707
references.citation: J Virol. 2000 Jun;74(11):4957-66
references.pmid: 10799569
references.citation: J Immunol. 2005 Apr 15;174(8):4465-9
references.pmid: 15814665
references.citation: J Immunol. 2007 Feb 15;178(4):2182-91
references.pmid: 17277123
references.citation: Blood. 2007 Feb 1;109(3):1113-22
references.pmid: 17018853
references.citation: Transgenic Res. 1999 Aug;8(4):265-77
references.pmid: 10621974
references.citation: J Immunol. 2005 Sep 15;175(6):3946-54
references.pmid: 16148142
references.citation: J Virol. 1999 Jan;73(1):783-6
references.pmid: 9847388
references.citation: PLoS Pathog. 2013 Oct;9(10):e1003723
references.pmid: 24204271
references.citation: Virol Monogr. 1977;(16):1-132
references.pmid: 337651
references.citation: Virol J. 2009 Jan 23;6:10
references.pmid: 19166574
references.citation: J Immunol. 2006 Mar 15;176(6):3315-9
references.pmid: 16517698
references.citation: Acta Virol. 1996 Jun;40(3):143-6
references.pmid: 8891094
references.citation: J Immunol. 2012 Dec 15;189(12):5877-85
references.pmid: 23152560
references.citation: Nat Rev Microbiol. 2010 Dec;8(12 Suppl):S7-16
references.pmid: 21079655
references.citation: J Immunol. 2006 Apr 15;176(8):4682-9
references.pmid: 16585561
references.citation: J Immunol. 2006 Apr 15;176(8):4525-9
references.pmid: 16585541
references.citation: J Virol. 2011 Aug;85(15):7775-87
references.pmid: 21632767
references.citation: Nature. 2013 Apr 25;496(7446):504-7
references.pmid: 23563266
references.citation: Arch Med Res. 2002 Jul-Aug;33(4):330-42
references.pmid: 12234522
references.citation: J Infect Dis. 2004 Mar 15;189(6):990-1000
references.pmid: 14999601
references.citation: J Virol. 2012 Dec;86(23):12561-70
references.pmid: 22973027
references.citation: PLoS Pathog. 2013;9(8):e1003521
references.pmid: 23935499
references.citation: Viruses. 2012 Jan;4(1):62-82
references.pmid: 22355452
references.citation: J Immunol. 2009 Apr 15;182(8):4865-73
references.pmid: 19342665
references.citation: J Immunol. 2006 Feb 15;176(4):2074-8
references.pmid: 16455962
references.citation: PLoS Pathog. 2010 Feb 12;6(2):e1000790
references.pmid: 20168989
references.citation: J Immunol. 2006 Aug 1;177(3):1746-54
references.pmid: 16849484
references.citation: J Gen Virol. 2010 Mar;91(Pt 3):697-706
references.pmid: 19889931
references.citation: Eur J Immunol. 2006 Aug;36(8):2094-105
references.pmid: 16810635
references.citation: J Virol. 2008 Dec;82(24):12312-24
references.pmid: 18842737
references.citation: Immunol Res. 2004;29(1-3):187-96
references.pmid: 15181281
references.citation: Immunity. 2003 Aug;19(2):225-34
references.pmid: 12932356
references.citation: Cell Host Microbe. 2010 Nov 18;8(5):410-21
references.pmid: 21075352
references.citation: J Exp Med. 2007 Jul 9;204(7):1653-64
references.pmid: 17591855
references.citation: PLoS Negl Trop Dis. 2010 Apr 27;4(4):e672
references.pmid: 20436920
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20435-9
references.pmid: 19918064
references.citation: Eur J Immunol. 2010 Oct;40(10):2769-77
references.pmid: 20821729
references.citation: J Virol. 2004 Mar;78(6):2701-10
references.pmid: 14990690
references.citation: N Engl J Med. 2012 Apr 12;366(15):1423-32
references.pmid: 22494122
references.citation: Nature. 2005 Feb 24;433(7028):887-92
references.pmid: 15711573
references.citation: Eur J Immunol. 2006 Aug;36(8):2046-60
references.pmid: 16856207
references.citation: Int Immunol. 2002 Apr;14(4):411-9
references.pmid: 11934877
references.citation: Antiviral Res. 2012 Sep;95(3):216-23
references.pmid: 22771779
references.citation: Lancet. 2012 Nov 3;380(9853):1559-67
references.pmid: 22975340
references.citation: Arch Virol. 2013 Jan;158(1):225-30
references.pmid: 22983185
references.citation: J Gen Virol. 2012 Oct;93(Pt 10):2152-2157
references.pmid: 22815273
references.citation: Vaccine. 2011 May 17;29(22):3895-904
references.pmid: 21443963
references.citation: J Clin Invest. 2002 Aug;110(3):321-30
references.pmid: 12163451
references.citation: Blood. 2006 Nov 15;108(10):3253-61
references.pmid: 16868248
references.citation: Immunity. 2001 Apr;14(4):461-70
references.pmid: 11336691
references.citation: Virology. 2009 Nov 25;394(2):249-58
references.pmid: 19783271
references.citation: Immunol Today. 1996 Aug;17(8):369-72
references.pmid: 8783497
references.citation: J Exp Med. 2005 Sep 5;202(5):637-50
references.pmid: 16129706