Rift Valley Fever Virus NSs Protein Promotes Post-Transcriptional Downregulation of Protein Kinase PKR and Inhibits eIF2α Phosphorylation

Abstract

Rift Valley fever virus (RVFV) (genus Phlebovirus, family Bunyaviridae) is a negative-stranded RNA virus with a tripartite genome. RVFV is transmitted by mosquitoes and causes fever and severe hemorrhagic illness among humans, and fever and high rates of abortions in livestock. A nonstructural RVFV NSs protein inhibits the transcription of host mRNAs, including interferon-β mRNA, and is a major virulence factor. The present study explored a novel function of the RVFV NSs protein by testing the replication of RVFV lacking the NSs gene in the presence of actinomycin D (ActD) or α-amanitin, both of which served as a surrogate of the host mRNA synthesis suppression function of the NSs. In the presence of the host-transcriptional inhibitors, the replication of RVFV lacking the NSs protein, but not that carrying NSs, induced double-stranded RNA-dependent protein kinase (PKR)–mediated eukaryotic initiation factor (eIF)2α phosphorylation, leading to the suppression of host and viral protein translation. RVFV NSs promoted post-transcriptional downregulation of PKR early in the course of the infection and suppressed the phosphorylated eIF2α accumulation. These data suggested that a combination of RVFV replication and NSs-induced host transcriptional suppression induces PKR-mediated eIF2α phosphorylation, while the NSs facilitates efficient viral translation by downregulating PKR and inhibiting PKR-mediated eIF2α phosphorylation. Thus, the two distinct functions of the NSs, i.e., the suppression of host transcription, including that of type I interferon mRNAs, and the downregulation of PKR, work together to prevent host innate antiviral functions, allowing efficient replication and survival of RVFV in infected mammalian hosts.

Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells

“…The S (small) segment encodes the N protein and a second nonstructural protein, NSs. NSs, a viral virulence factor, is a transcriptional repressor critical to the down-regulation of the host interferon response (7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

A Glycoprotein Subunit Vaccine Elicits a Strong Rift Valley Fever Virus Neutralizing Antibody Response in Sheep

“…The N and L proteins are required for viral RNA synthesis. The NSs protein, the major virulence factor, has been shown to inhibit host transcriptional immune response (Bouloy et al 2001) through generalized transcription downregulation, including repression of interferon-b (IFN-b) , Le May et al 2004, Le May et al 2008) and degradation of protein kinase R , Ikegami et al 2009). The NSm protein functions to suppress virus-induced apoptosis (Won et al 2007), and there is evidence that it plays a functional role in the vector competence of mosquitos for RVFV at the level of the midgut barrier (Kading et al 2014).…”

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