Viperin, MTAP44, and protein kinase R contribute to the interferon-induced inhibition of Bunyamwera Orthobunyavirus replication.
The first line of defense against viral infection is the interferon (IFN) response, which culminates in the expression of hundreds of proteins with presumed antiviral activity, and must be overcome by a virus for successful replication. The nonstructural NSs protein is the primary IFN antagonist encoded by Bunyamwera virus (BUNV), the prototype of the Orthobunyavirus genus and the family Bunyaviridae. The NSs protein interferes with RNA polymerase II-mediated transcription, thereby inhibiting cellular mRNA production, including IFN mRNAs. A recombinant virus, rBUNdelNSs, that is unable to express the NSs protein does not inhibit cellular transcription and is a strong IFN inducer. We report here that cells stimulated into the antiviral state by IFN-β treatment were protected against wild-type BUNV and rBUNdelNSs infection but addition of IFN-β after infection had little effect on the replication cycle of either virus. By screening a panel of cell lines that overexpressed individual IFN-stimulated genes, we found that protein kinase R (PKR), MTAP44, and particularly viperin appreciably restricted BUNV replication. The enzymatic activities of PKR and viperin were required for their inhibitory activities. Taken together, our data show that the restriction of BUNV replication mediated by IFN is an accumulated effect of at least three IFN-stimulated genes that probably act on different stages of the viral replication cycle.
Biomedical Sciences Research Complex, School of Biology, University of St. Andrews, North Haugh, St. Andrews, Scotland, United Kingdom.
Charles
C
Carlton-Smith
Richard M
RM
Elliott
D000818:Animals; D000941:Antigens / Q000378:metabolism*; D002042:Bunyamwera virus / Q000276:immunology*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000276:immunology*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins / Q000378:metabolism*; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism*; D000090123:Viperin Protein
D000941:Antigens; D003598:Cytoskeletal Proteins; D007372:Interferons; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D019892:eIF-2 Kinase; C065888:IFI44 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein