Abstract
Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, causes periodic outbreaks in livestocks and humans in countries of the African continent and Middle East. RVFV NSs protein, a nonstructural protein, is a major virulence factor that exhibits several important biological properties. These include suppression of general transcription, inhibition of IFN-β promoter induction and degradation of double-stranded RNA-dependent protein kinase R. Although each of these biological functions of NSs are considered important for countering the antiviral response in the host, the individual contributions of these functions towards RVFV virulence remains unclear. To examine this, we generated two RVFV MP-12 strain-derived mutant viruses. Each carried mutations in NSs that specifically targeted its general transcription inhibition function without affecting its ability to degrade PKR and inhibit IFN-β promoter induction, through its interaction with Sin3-associated protein 30, a part of the repressor complex at the IFN-β promoter. Using these mutant viruses, we have dissected the transcription inhibition function of NSs and examined its importance in RVFV virulence. Both NSs mutant viruses exhibited a differentially impaired ability to inhibit host transcription when compared with MP-12. It has been reported that NSs suppresses general transcription by interfering with the formation of the transcription factor IIH complex, through the degradation of the p62 subunit and sequestration of the p44 subunit. Our study results lead us to suggest that the ability of NSs to induce p62 degradation is the major contributor to its general transcription inhibition property, whereas its interaction with p44 may not play a significant role in this function. Importantly, RVFV MP-12-NSs mutant viruses with an impaired general transcription inhibition function showed a reduced cytotoxicity in cell culture and attenuated virulence in young mice, compared with its parental virus MP-12, highlighting the contribution of NSs-mediated general transcription inhibition towards RVFV virulence.
Highlights
Rift Valley fever virus (RVFV) is the pathogen causing Rift Valley fever, which affects both humans and domestic ruminants, primarily in countries of the African continent and Middle East
We previously generated and characterized an RVFV MP-12 strain-derived mutant virus, which is deficient for efficient virus genome co-packaging due to a large deletion in the 5’ untranslated region of M RNA segment [30]
We examined the effect of differences in the transcription inhibitory activities of the mutant viruses on global protein synthesis by incorporation of 35S-methionine/cysteine into newly synthesizing proteins in mock-infected cells and in cells infected with MP-12, MP12ΔNSs, MP-12-M250K, or MP-12-R16H/M250K (Fig 2C)
Summary
Rift Valley fever virus (RVFV) is the pathogen causing Rift Valley fever, which affects both humans and domestic ruminants, primarily in countries of the African continent and Middle East. The virus is an arbovirus and circulates between mosquito vectors and ruminants in endemic areas. Humans are infected with the virus either by mosquito bite or by direct contact with materials of infected animals. The majority of patients show influenzalike symptoms but few develop hemorrhagic fever, neurological symptoms, and ocular disease [2]. Due to its major impact on public health, RVFV is classified as a category A priority pathogen by the National Institute of Allergy and Infectious Diseases. There is no approved vaccine available for humans and animals in non-endemic areas
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