title: Effects of PKR/RNase L-dependent and alternative antiviral pathways on alphavirus replication and pathogenesis.
abstract: Type I interferons (IFN-alpha/beta) rapidly confer resistance to alphavirus infection in macrophages and dendritic cells (DC) as evidenced by the dramatically increased susceptibility of these cells in mice with the IFNAR1 subunit of the IFN-alpha/beta receptor ablated (IFNAR1-/-). Normal adult mice develop only a subclinical Sindbis virus infection, whereas infected IFNAR1-/- mice rapidly succumb to a fatal disease. Here, we investigated the individual and combined contributions of the two best characterized INF-alpha/beta-mediated antiviral pathways to the control of Sindbis virus replication: (1) the coupled 2-5A synthetase/RNase L pathway and (2) the double-stranded RNA-dependent protein kinase (PKR) pathway. Surprisingly, mice deficient in PKR, RNase L, and Mx-1 (triply-deficient [TD]) developed only subclinical infection. Although the permissivity of cells in lymph nodes draining the inoculation site was increased in the absence of PKR/RNase L, systemic dissemination of the virus infection was restricted by an alternative IFN-alpha/beta receptor-dependent mechanism. In vitro, suppression of early virus protein synthesis and virion production in primary bone marrow-derived dendritic cells (BMDC) was largely dependent on the PKR pathway. However, later in infection virion production was reduced even in the absence of PKR/RNase L by an IFN-alpha/beta receptor-dependent mechanism. Priming of BMDC with IFN-alpha/beta or IFN-gamma resulted in dose-dependent restriction of virus replication, largely independent of PKR and/or RNase L expression.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, USA.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Ryman
authors.forename: Laura J
authors.initials: LJ
authors.lastname: White
authors.forename: Robert E
authors.initials: RE
authors.lastname: Johnston
authors.forename: William B
authors.initials: WB
authors.lastname: Klimstra
mesh_terms: D018354:Alphavirus Infections / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004722:Endoribonucleases / Q000502:physiology*; D016898:Interferon-alpha / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology*; D051379:Mice; D012845:Sindbis Virus / Q000472:pathogenicity / Q000502:physiology*; D014771:Virion / Q000502:physiology; D014774:Virulence; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D016898:Interferon-alpha; D016899:Interferon-beta; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease