title: Gamma interferon plays a crucial early antiviral role in protection against West Nile virus infection.
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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, St. Louis, MO 63110, USA.
authors.forename: Bimmi
authors.initials: B
authors.lastname: Shrestha
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Samuel
authors.forename: Kevin
authors.initials: K
authors.lastname: Whitby
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014901:West Nile Fever / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014902:West Nile virus / Q000235:genetics* / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D000998:Antiviral Agents; D007371:Interferon-gamma