NSs protein of rift valley fever virus induces the specific degradation of the double-stranded RNA-dependent protein kinase.
Rift Valley fever virus (RVFV) continues to cause large outbreaks of acute febrile and often fatal illness among humans and domesticated animals in Africa, Saudi Arabia, and Yemen. The high pathogenicity of this bunyavirus is mainly due to the viral protein NSs, which was shown to prevent transcriptional induction of the antivirally active type I interferons (alpha/beta interferon [IFN-alpha/beta]). Viruses lacking the NSs gene induce synthesis of IFNs and are therefore attenuated, whereas the noninducing wild-type RVFV strains can only be inhibited by pretreatment with IFN. We demonstrate here in vitro and in vivo that a substantial part of the antiviral activity of IFN against RVFV is due to a double-stranded RNA-dependent protein kinase (PKR). PKR-mediated virus inhibition, however, was much more pronounced for the strain Clone 13 with NSs deleted than for the NSs-expressing strain ZH548. In vivo, Clone 13 was nonpathogenic for wild-type (wt) mice but could regain pathogenicity if mice lacked the PKR gene. ZH548, in contrast, killed both wt and PKR knockout mice indiscriminately. ZH548 was largely resistant to the antiviral properties of PKR because RVFV NSs triggered the specific degradation of PKR via the proteasome. The NSs proteins of the related but less virulent sandfly fever Sicilian virus and La Crosse virus, in contrast, had no such anti-PKR activity despite being efficient suppressors of IFN induction. Our data suggest that RVFV NSs has gained an additional anti-IFN function that may explain the extraordinary pathogenicity of this virus.
Habjan
Matthias
M
Department of Virology, University of Freiburg, Freiburg, Germany.
Pichlmair
Andreas
A
Elliott
Richard M
RM
Overby
Anna K
AK
Glatter
Timo
T
Gstaiger
Matthias
M
Superti-Furga
Giulio
G
Unger
Hermann
H
Weber
Friedemann
F
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012330:RNA, Double-Stranded; D012296:Rift Valley fever virus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000998:Antiviral Agents; D012330:RNA, Double-Stranded; D017361:Viral Nonstructural Proteins; D007372:Interferons; D019892:eIF-2 Kinase; D046988:Proteasome Endopeptidase Complex