The severe acute respiratory syndrome coronavirus (SARS-CoV) nsp1 protein has unique biological functions that have not been described in the viral proteins of any RNA viruses; expressed SARS-CoV nsp1 protein has been found to suppress host gene expression by promoting host mRNA degradation and inhibiting translation. We generated an nsp1 mutant (
Rift Valley fever virus (RVFV) (genus Phlebovirus, family Bunyaviridae) has a tripartite negative-strand genome, causes a mosquito-borne disease that is endemic in sub-Saharan African countries and that also causes large epidemics among humans and livestock. Furthermore, it is a bioterrorist threat and poses a risk for introduction to other areas. In spite of its danger, neither veterinary nor human vaccines are available. We established a T7 RNA polymerase-driven reverse genetics system to rescue infectious clones of RVFV MP-12 strain entirely from cDNA, the first for any phlebovirus.
Rift Valley fever (RVF) is an emerging zoonotic disease distributed in sub-Saharan African countries and the Arabian Peninsula. The disease is caused by the Rift Valley fever virus (RVFV) of the family Bunyaviridae and the genus Phlebovirus. The virus is transmitted by mosquitoes, and virus replication in domestic ruminant results in high rates of mortality and abortion. RVFV infection in humans usually causes a self-limiting, acute and febrile illness; however, a small number of cases progress to neurological disorders, partial or complete blindness, hemorrhagic fever, or thrombosis. This review describes the pathology of RVF in human patients and several animal models, and summarizes the role of viral virulence factors and host factors that affect RVFV pathogenesis.
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.
Rift Valley fever virus (RVFV) is a member of the genus Rift Valley fever virus (RVFV), a member of the genusPhlebovirus within the family Bunyaviridae, causes periodic outbreaks among livestock and humans in sub-Saharan African countries (42). RVFV infection results in severe hepatic diseases, with high mortality and abortion rates, in domestic ruminants and also causes an acute febrile myalgic syndrome, a hemorrhagic syndrome, ocular disease, and encephalitis in humans (3, 39). The most recent outbreak was reported in Kenya and resulted in a high reported case-fatality ratio for infected humans (12). RVFV is transmitted primarily by mosquitoes or through direct contact with infected animal blood. Even though the natural infectious cycle of RVFV has been linked to mosquitoes of Aedes species, many other mosquito species can be infected and subsequently transmit the virus (16), implying that these mosquito species can increase the possibility of RVFV becoming epidemic and perhaps endemic outside of its traditional area.RVFV has a single-stranded, tripartite RNA genome composed of the L, M, and S segments. The L segment is of negative polarity and encodes the RNA-dependent RNA polymerase (L). The S segment uses an ambisense strategy for gene expression; a nonstructural protein, NSs, is translated from viral-sense mRNA, while the nucleocapsid (N) protein is expressed from anti-viral-sense mRNA (42). The NSs protein has been known as an interferon antagonist due to its shutting off of host transcription (5, 34). The anti-viral-sense M segment encodes two envelope glycoproteins, Gn and Gc, and two accessory proteins, the 14-kDa NSm protein and the 78-kDa protein.The M gene open reading frame (ORF) in M mRNA contains five in-frame translation initiation codons within the preglycoprotein (pre-Gn) region, which is located upstream of the Gn and Gc genes (see Fig. 1A) (20,26,48). The 78-kDa protein is translated from the first AUG codon of the ORF, and its coding sequence includes the entire NSm and Gn coding sequences. NSm is translated from the region from the second AUG codon to the end of the pre-Gn region (see Fig. 1). The NSm and 78-kDa proteins are not essential for RVFV replication in cell culture (18, 51), whereas all RVFVs thus far sequenced carry the pre-Gn region (7), strongly suggesting that there is selection pressure(s) to retain an RNA element(s) in the pre-Gn region and/or proteins encoded (fully or partially) by the pre-Gn region, i.e., NSm and the 78-kDa protein. Currently, the biological functions of the NSm and 78-kDa proteins of RVFV and proteins encoded by the pre-Gn regions of other phleboviruses are totally unclear, though a mutant RVFV lacking both NSm and 78-kDa protein expression showed attenuated virulence in rats (6), implying a possible role of the RVFV NSm and/or 78-kDa protein in viral pathogenesis.In the present study, we have generated a deletion mutant of an attenuated MP-12 strain of RVFV, which expresses neither the NSm protein nor the 78-kDa protein, due to a large deletion in the...
Rift Valley fever virus (RVFV; family Bunyaviridae, genus Phlebovirus) is an important emerging pathogen of humans and ruminants. Its NSs protein has previously been identified as a major virulence factor that suppresses host defense through three distinct mechanisms: it directly inhibits beta interferon (IFN-) promoter activity, it promotes the degradation of double-stranded RNA-dependent protein kinase (PKR), and it suppresses host transcription by disrupting the assembly of the basal transcription factor TFIIH through sequestration of its p44 subunit. Here, we report that in addition to PKR, NSs also promotes the degradation of the TFIIH subunit p62. Infection of cells with the RVFV MP-12 vaccine strain reduced p62 protein levels to below the detection limit early in the course of infection. This NSs-mediated downregulation of p62 was posttranslational, as it was unaffected by pharmacological inhibition of transcription or translation and MP-12 infection had no effect on p62 mRNA levels. Treatment of cells with proteasome inhibitors but not inhibition of lysosomal acidification or nuclear export resulted in a stabilization of p62 in the presence of NSs. Furthermore, p62 could be coprecipitated with NSs from lysates of infected cells. These data suggest that the RVFV NSs protein is able to interact with the TFIIH subunit p62 inside infected cells and promotes its degradation, which can occur directly in the nucleus.
Rift Valley fever virus (RVFV), which belongs to the genus Phlebovirus, family Bunyaviridae, is a negative-stranded RNA virus carrying a tripartite RNA genome. RVFV is transmitted by mosquitoes and causes large outbreaks among ruminants and humans in Africa and the Arabian Peninsula. Human patients develop an acute febrile illness, followed by a fatal hemorrhagic fever, encephalitis or ocular diseases, whereas ruminants experience abortions during outbreak. Effective vaccination of both humans and ruminants is the best approach to control Rift Valley fever. This article summarizes the development of inactivated RVFV vaccine, live attenuated vaccine, and other new generation vaccines.
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