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PMID: 16699014 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Gamma interferon plays a crucial early antiviral role in protection against West Nile virus infection.

Journal of virology ·Vol. 80 ·No. 11 ·2006-06-00 ·Pages 5338-48

Shrestha B, Wang T, Samuel MA, Whitby K, Craft J, Fikrig E, Diamond MS

Abstract

West Nile virus (WNV) causes a severe central nervous system (CNS) infection in humans, primarily in the elderly and immunocompromised. Prior studies have established an essential protective role of several innate immune response elements, including alpha/beta interferon (IFN-alpha/beta), immunoglobulin M, gammadelta T cells, and complement against WNV infection. In this study, we demonstrate that a lack of IFN-gamma production or signaling results in increased vulnerability to lethal WNV infection by a subcutaneous route in mice, with a rise in mortality from 30% (wild-type mice) to 90% (IFN-gamma(-/-) or IFN-gammaR(-/-) mice) and a decrease in the average survival time. This survival pattern in IFN-gamma(-/-) and IFN-gammaR(-/-) mice correlated with higher viremia and greater viral replication in lymphoid tissues. The increase in peripheral infection led to early CNS seeding since infectious WNV was detected several days earlier in the brains and spinal cords of IFN-gamma(-/-) or IFN-gammaR(-/-) mice. Bone marrow reconstitution experiments showed that gammadelta T cells require IFN-gamma to limit dissemination by WNV. Moreover, treatment of primary dendritic cells with IFN-gamma reduced WNV production by 130-fold. Collectively, our experiments suggest that the dominant protective role of IFN-gamma against WNV is antiviral in nature, occurs in peripheral lymphoid tissues, and prevents viral dissemination to the CNS.

MeSH Terms
Animals Antiviral Agents/pharmacology,therapeutic use Interferon-gamma/physiology Mice Mice, Inbred C57BL West Nile Fever/immunology,prevention & control,virology West Nile virus/genetics,growth & development,immunology,pathogenicity
Chemicals
Antiviral Agents Interferon-gamma
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Shrestha Bimmi
Department of Medicine, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, St. Louis, MO 63110, USA.
Wang Tian
Samuel Melanie A
Whitby Kevin
Craft Joe
Fikrig Erol
Diamond Michael S
References (70)
70 references, click to expand
  1. Human dendritic cells as targets of dengue virus infection.
    J Investig Dermatol Symp Proc. 2001 Dec;6(3):219-24 PMID: 11924831
  2. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis.
    Nat Med. 2004 Dec;10(12):1366-73 PMID: 15558055
  3. Positional cloning of the murine flavivirus resistance gene.
    Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9322-7 PMID: 12080145
  4. Yellow fever virus encephalitis: properties of the brain-associated T-cell response during virus clearance in normal and gamma interferon-deficient mice and requirement for CD4+ lymphocytes.
    J Virol. 2001 Mar;75(5):2107-18 PMID: 11160715
  5. Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production.
    J Immunol. 2001 Feb 1;166(3):1499-506 PMID: 11160189
  6. Interferon-gamma-mediated site-specific clearance of alphavirus from CNS neurons.
    Science. 2001 Jul 13;293(5528):303-6 PMID: 11452126
  7. Interleukin-1beta but not tumor necrosis factor is involved in West Nile virus-induced Langerhans cell migration from the skin in C57BL/6 mice.
    J Invest Dermatol. 2001 Sep;117(3):702-9 PMID: 11564180
  8. Enhanced virus replication and inhibition of lymphocytic choriomeningitis virus disease in anti-gamma interferon-treated mice.
    J Virol. 1989 Jun;63(6):2813-9 PMID: 2542591
  9. Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection.
    J Exp Med. 2005 Oct 17;202(8):1087-98 PMID: 16230476
  10. Gamma interferon is critical for neuronal viral clearance and protection in a susceptible mouse strain following early intracranial Theiler's murine encephalomyelitis virus infection.
    J Virol. 2003 Nov;77(22):12252-65 PMID: 14581562
  11. West Nile fever--a reemerging mosquito-borne viral disease in Europe.
    Emerg Infect Dis. 1999 Sep-Oct;5(5):643-50 PMID: 10511520
  12. Modulation of Dengue virus infection in human cells by alpha, beta, and gamma interferons.
    J Virol. 2000 Jun;74(11):4957-66 PMID: 10799569
  13. A nonsense mutation in the gene encoding 2'-5'-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice.
    Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11311-6 PMID: 12186974
  14. Gamma interferon expression during acute and latent nervous system infection by herpes simplex virus type 1.
    J Virol. 1995 Aug;69(8):4898-905 PMID: 7609058
  15. Single nucleotide polymorphisms in genes for 2'-5'-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection.
    J Infect Dis. 2005 Nov 15;192(10):1741-8 PMID: 16235172
  16. Antibody prophylaxis and therapy against West Nile virus infection in wild-type and immunodeficient mice.
    J Virol. 2003 Dec;77(24):12941-9 PMID: 14645550
  17. West Nile poliomyelitis.
    Lancet Infect Dis. 2003 Jan;3(1):9-10 PMID: 12505023
  18. Gamma interferon-dependent, noncytolytic clearance of sindbis virus infection from neurons in vitro.
    J Virol. 2005 May;79(9):5374-85 PMID: 15827152
  19. Gamma delta T cells provide an early source of interferon gamma in tumor immunity.
    J Exp Med. 2003 Aug 4;198(3):433-42 PMID: 12900519
  20. Role of CD8+ T cells in control of West Nile virus infection.
    J Virol. 2004 Aug;78(15):8312-21 PMID: 15254203
  21. Interferon-gamma induced type I nitric oxide synthase activity inhibits viral replication in neurons.
    J Neuroimmunol. 1996 Aug;68(1-2):101-8 PMID: 8784266
  22. Interferon-gamma-induced inhibition of neuronal vesicular stomatitis virus infection is STAT1 dependent.
    J Neurovirol. 2004 Feb;10(1):57-63 PMID: 14982729
  23. Role of type I and type II interferon responses in recovery from infection with an encephalitic flavivirus.
    J Gen Virol. 2003 Mar;84(Pt 3):567-572 PMID: 12604807
  24. Inhibition of Japanese encephalitis virus infection by nitric oxide: antiviral effect of nitric oxide on RNA virus replication.
    J Virol. 1997 Jul;71(7):5227-35 PMID: 9188590
  25. Gamma interferon is a major mediator of antiviral defense in experimental measles virus-induced encephalitis.
    J Virol. 1995 Sep;69(9):5469-74 PMID: 7636992
  26. Replication of West Nile virus in equine peripheral blood mononuclear cells.
    Vet Immunol Immunopathol. 2006 Apr 15;110(3-4):229-44 PMID: 16310859
  27. CD8+ T cells mediate recovery and immunopathology in West Nile virus encephalitis.
    J Virol. 2003 Dec;77(24):13323-34 PMID: 14645588
  28. The role of IFN-gamma in immune responses to viral infections of the central nervous system.
    Cytokine Growth Factor Rev. 2002 Dec;13(6):441-54 PMID: 12401479
  29. Perforin-mediated effector function within the central nervous system requires IFN-gamma-mediated MHC up-regulation.
    J Immunol. 2003 Mar 15;170(6):3204-13 PMID: 12626579
  30. A poliomyelitis-like syndrome from West Nile virus infection.
    N Engl J Med. 2002 Oct 17;347(16):1279-80 PMID: 12270971
  31. Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival.
    J Virol. 2005 Nov;79(21):13350-61 PMID: 16227257
  32. Experimental encephalitis following peripheral inoculation of West Nile virus in mice of different ages.
    J Hyg (Lond). 1970 Sep;68(3):435-46 PMID: 4917916
  33. Mouse neuroinvasive phenotype of West Nile virus strains varies depending upon virus genotype.
    Virology. 2002 Apr 25;296(1):17-23 PMID: 12036314
  34. Immune-mediated protection from measles virus-induced central nervous system disease is noncytolytic and gamma interferon dependent.
    J Virol. 2002 May;76(9):4497-506 PMID: 11932415
  35. Disassociation between the in vitro and in vivo effects of nitric oxide on a neurotropic murine coronavirus.
    J Virol. 1997 Mar;71(3):2202-10 PMID: 9032354
  36. Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis.
    J Virol. 2001 Apr;75(8):3501-8 PMID: 11264339
  37. West Nile virus: crossing the blood-brain barrier.
    Nat Med. 2004 Dec;10(12):1294-5 PMID: 15580248
  38. Immune-mediated clearance of virus from the central nervous system.
    Microbes Infect. 2003 Apr;5(5):439-48 PMID: 12738000
  39. Perforin and gamma interferon-mediated control of coronavirus central nervous system infection by CD8 T cells in the absence of CD4 T cells.
    J Virol. 2004 Feb;78(4):1739-50 PMID: 14747539
  40. West Nile encephalitis epidemic in southeastern Romania.
    Lancet. 1998 Sep 5;352(9130):767-71 PMID: 9737281
  41. Innate and adaptive immune responses determine protection against disseminated infection by West Nile encephalitis virus.
    Viral Immunol. 2003;16(3):259-78 PMID: 14583143
  42. Interferon-gamma: an overview of signals, mechanisms and functions.
    J Leukoc Biol. 2004 Feb;75(2):163-89 PMID: 14525967
  43. Antiviral effect of nitric oxide during Japanese encephalitis virus infection.
    Int J Exp Pathol. 2000 Apr;81(2):165-72 PMID: 10762444
  44. Dendritic cells process and present antigens across a range of maturation states.
    J Immunol. 2003 Jun 1;170(11):5367-72 PMID: 12759410
  45. Phenotypic changes in Langerhans' cells after infection with arboviruses: a role in the immune response to epidermally acquired viral infection?
    J Virol. 1996 Jul;70(7):4761-6 PMID: 8676503
  46. Pathogenesis and clinical features of Japanese encephalitis and West Nile virus infections.
    Curr Top Microbiol Immunol. 2002;267:171-94 PMID: 12082989
  47. Interferon-dependent immunity is essential for resistance to primary dengue virus infection in mice, whereas T- and B-cell-dependent immunity are less critical.
    J Virol. 2004 Mar;78(6):2701-10 PMID: 14990690
  48. Pathogenesis of West Nile Virus encephalitis in mice and rats. 1. Influence of age and species on mortality and infection.
    Am J Epidemiol. 1967 Nov;86(3):765-75 PMID: 6081390
  49. The West Nile Virus outbreak of 1999 in New York: the Flushing Hospital experience.
    Clin Infect Dis. 2000 Mar;30(3):413-8 PMID: 10722421
  50. IFN-gamma-producing gamma delta T cells help control murine West Nile virus infection.
    J Immunol. 2003 Sep 1;171(5):2524-31 PMID: 12928402
  51. CCR5 deficiency increases risk of symptomatic West Nile virus infection.
    J Exp Med. 2006 Jan 23;203(1):35-40 PMID: 16418398
  52. West Nile virus infection in the golden hamster (Mesocricetus auratus): a model for West Nile encephalitis.
    Emerg Infect Dis. 2001 Jul-Aug;7(4):714-21 PMID: 11585537
  53. Critical role for the oligoadenylate synthetase/RNase L pathway in response to IFN-beta during acute ocular herpes simplex virus type 1 infection.
    J Immunol. 2005 Jul 15;175(2):1100-6 PMID: 16002711
  54. Induction of nitric oxide synthase during Japanese encephalitis virus infection: evidence of protective role.
    Arch Biochem Biophys. 2001 Jul 1;391(1):1-7 PMID: 11414678
  55. Immunity to West Nile virus.
    Curr Opin Immunol. 2004 Aug;16(4):519-23 PMID: 15245749
  56. Prophylactic and therapeutic efficacy of human intravenous immunoglobulin in treating West Nile virus infection in mice.
    J Infect Dis. 2003 Jul 1;188(1):5-12 PMID: 12825165
  57. West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection.
    J Virol. 2006 Feb;80(3):1290-301 PMID: 16415006
  58. Neuronal CXCL10 directs CD8+ T-cell recruitment and control of West Nile virus encephalitis.
    J Virol. 2005 Sep;79(17):11457-66 PMID: 16103196
  59. Pathology of fatal West Nile virus infections in native and exotic birds during the 1999 outbreak in New York City, New York.
    Vet Pathol. 2000 May;37(3):208-24 PMID: 10810985
  60. B cells and antibody play critical roles in the immediate defense of disseminated infection by West Nile encephalitis virus.
    J Virol. 2003 Feb;77(4):2578-86 PMID: 12551996
  61. The critical role of IFN-gamma in experimental coronavirus retinopathy.
    Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3402-8 PMID: 12882788
  62. Human skin Langerhans cells are targets of dengue virus infection.
    Nat Med. 2000 Jul;6(7):816-20 PMID: 10888933
  63. New mouse model for dengue virus vaccine testing.
    J Virol. 1999 Jan;73(1):783-6 PMID: 9847388
  64. Loss of active neuroinvasiveness in attenuated strains of West Nile virus: pathogenicity in immunocompetent and SCID mice.
    Arch Virol. 1994;137(3-4):355-70 PMID: 7944955
  65. CD8+ T cells require perforin to clear West Nile virus from infected neurons.
    J Virol. 2006 Jan;80(1):119-29 PMID: 16352536
  66. Noncytolytic control of viral infections by the innate and adaptive immune response.
    Annu Rev Immunol. 2001;19:65-91 PMID: 11244031
  67. Development of effective therapies against West Nile virus infection.
    Expert Rev Anti Infect Ther. 2005 Dec;3(6):931-44 PMID: 16307506
  68. Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus.
    Nat Med. 2005 May;11(5):522-30 PMID: 15852016
  69. Pathogenesis of West Nile Virus encepahlitis in mice and rats. II. Virus multiplication, evolution of immunofluorescence, and development of histological lesions in the brain.
    Am J Epidemiol. 1967 Nov;86(3):776-90 PMID: 4866286
  70. Langerhans cells migrate to local lymph nodes following cutaneous infection with an arbovirus.
    J Invest Dermatol. 2000 Mar;114(3):560-8 PMID: 10692118
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.00274-06
Published
2006-06-00
Pages
5338-48
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC1472130
Subset
IM
External Links
PubMed source DOI: 10.1128/JVI.00274-06 PMC Full Text View journal details
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