scholarly journals A Hyper-Attenuated Variant of Rift Valley Fever Virus Generated by a Mutagenic Drug (Favipiravir) Unveils Potential Virulence Markers

2021 ◽  
Vol 11 ◽  
Author(s):  
Belén Borrego ◽  
Alejandro Brun
Keyword(s):  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Economic Losses ◽  
Type I ◽  
Valley Fever ◽  
Virulence Markers ◽  
Drug Concentrations

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes Rift Valley fever (RVF), a zoonotic disease of wild and domestic ruminants, causing serious economic losses and a threat to human health that could be controlled by vaccination. Though RVF vaccines are available for livestock, no RVF vaccines have been licensed for veterinary use in non-endemic countries nor for human populations in RVF risk areas. In a recent work, we showed that favipiravir, a promising drug with antiviral activity against a number of RNA viruses, led to the extinction of RVFV from infected cell cultures. Nevertheless, certain drug concentrations allowed the recovery of a virus variant showing increased resistance to favipiravir. In this work, we characterized this novel resistant variant both at genomic and phenotypic level in vitro and in vivo. Interestingly, the resistant virus displayed reduced growth rates in C6/36 insect cells but not in mammalian cell lines, and was highly attenuated but still immunogenic in vivo. Some amino acid substitutions were identified in the viral RNA-dependent RNA-polymerase (RdRp) gene and in the virus encoded type I-interferon (IFN-I) antagonist NSs gene, in catalytic core motifs and nuclear localization associated positions, respectively. These data may help to characterize novel potential virulence markers, offering additional strategies for further safety improvements of RVF live attenuated vaccine candidates.

scholarly journals The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice Not Related with a Type-I IFN Antagonistic Phenotype

2021 ◽  
Author(s):  
Belén Borrego ◽  
Sandra Moreno ◽  
Nuria de la Losa ◽  
Friedemann Weber ◽  
Alejandro Brun
Keyword(s):  
Amino Acid ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Single Amino Acid ◽  
Economic Losses ◽  
Type I ◽  
Valley Fever

Rift valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes an important disease in ruminants, with great economic losses. The infection can be also transmitted to humans; therefore it is considered a major threat to both human and animal health. In a previous work, we described a novel RVFV variant selected in cell culture in the presence of the antiviral agent favipiravir that was highly attenuated in vivo. This variant displayed 24 amino acid substitutions in different viral proteins when compared to its parental viral strain, two of them located in the NSs protein that is known to be the major virulence factor of RVFV. By means of a reverse genetics system, in this work we have analyzed the effect that one of these substitutions, P82L, has in viral attenuation in vivo. Rescued viruses carrying this single amino acid change were clearly attenuated in BALB/c mice while their growth in an IFN-competent cell line as well as the production of IFN-β did not seem to be affected. However, the pattern of nuclear NSs accumulation was modified in cells infected with the mutant viruses. These results unveil a new RVFV virulence marker highlighting the multiple ways of NSs protein to modulate viral infectivity.

scholarly journals The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 542
Author(s):  
Belén Borrego ◽  
Sandra Moreno ◽  
Nuria de la Losa ◽  
Friedemann Weber ◽  
Alejandro Brun
Keyword(s):  
Amino Acid ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Single Amino Acid ◽  
Economic Losses ◽  
Valley Fever ◽  
Single Amino Acid Change

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes an important disease in ruminants, with great economic losses. The infection can be also transmitted to humans; therefore, it is considered a major threat to both human and animal health. In a previous work, we described a novel RVFV variant selected in cell culture in the presence of the antiviral agent favipiravir that was highly attenuated in vivo. This variant displayed 24 amino acid substitutions in different viral proteins when compared to its parental viral strain, two of them located in the NSs protein that is known to be the major virulence factor of RVFV. By means of a reverse genetics system, in this work we have analyzed the effect that one of these substitutions, P82L, has in viral attenuation in vivo. Rescued viruses carrying this single amino acid change were clearly attenuated in BALB/c mice while their growth in an interferon (IFN)-competent cell line as well as the production of interferon beta (IFN-β) did not seem to be affected. However, the pattern of nuclear NSs accumulation was modified in cells infected with the mutant viruses. These results highlight the key role of the NSs protein in the modulation of viral infectivity.

scholarly journals Preliminary Evaluation of a Bunyavirus Vector for Cancer Immunotherapy

2015 ◽  
Vol 89 (17) ◽  
pp. 9124-9127 ◽  
Author(s):  
N. Oreshkova ◽  
L. Spel ◽  
R. P. M. Vloet ◽  
P. J. Wichgers Schreur ◽  
R. J. M. Moormann ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Preliminary Evaluation ◽  
Valley Fever ◽  
Human Dendritic Cells

Replicon particles of Rift Valley fever virus, referred to as nonspreading Rift Valley fever virus (NSR), are intrinsically safe and highly immunogenic. Here, we demonstrate that NSR-infected human dendritic cells can activate CD8+T cellsin vitroand that prophylactic and therapeutic vaccinations of mice with NSR encoding a tumor-associated CD8 peptide can control the outgrowth of lymphoma cellsin vivo. These results suggest that the NSR system holds promise for cancer immunotherapy.

scholarly journals MAVS mediates a protective immune response in the brain to Rift Valley fever virus

2021 ◽  
Author(s):  
Dina R. Weilhammer ◽  
Nicholas R. Hum ◽  
Feliza A. Bourguet ◽  
Aimy Sebastian ◽  
Doris Lam ◽  
...  
Keyword(s):  
Immune Response ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Molecular Mechanisms ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Type I ◽  
Activation Markers ◽  
Valley Fever ◽  
The Brain

Rift Valley fever virus (RVFV) is a highly pathogenic mosquito-borne virus capable of causing hepatitis, encephalitis, blindness, hemorrhagic syndrome, and death in humans and livestock. Upon aerosol infection with RVFV, the brain is a major site of viral replication and tissue damage, yet pathogenesis in this organ has been understudied. Here, we investigated the immune response in the brain of RVFV infected mice. In response to infection, microglia initiate robust transcriptional upregulation of antiviral immune genes, as well as increased levels of activation markers and cytokine secretion that is dependent on mitochondrial antiviral-signaling protein (MAVS) and independent of toll-like receptors 3 and 7. In vivo, Mavs-/- mice displayed enhanced susceptibility to RVFV as determined by increased brain viral burden and higher mortality. Single-cell RNA sequence analysis identified microglia-specific defects in type I interferon and interferon responsive gene expression in Mavs-/- mice, as well as dysregulated lymphocyte infiltration. The results of this study provide a crucial step towards understanding the precise molecular mechanisms by which RVFV infection is controlled in the brain and will help inform the development of vaccines and antiviral therapies that are effective in preventing encephalitis.

Comparison of in vitro and in vivo systems for propagation of rift valley fever virus from clinical specimens

1989 ◽  
Vol 140 ◽  
pp. 129-138 ◽  
Author(s):  
G.W. Anderson ◽  
J.-F. Saluzzo ◽  
T.G. Ksiazek ◽  
J.F. Smith ◽  
W. Ennis ◽  
...  
Keyword(s):  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Valley Fever ◽  
Clinical Specimens

scholarly journals Resistance to Rift Valley fever virus in Rattus norvegicus: genetic variability within certain ‘inbred’ strains

2000 ◽  
Vol 81 (11) ◽  
pp. 2683-2688 ◽  
Author(s):  
Marcus Ritter ◽  
Michèle Bouloy ◽  
Pierre Vialat ◽  
Christian Janzen ◽  
Otto Haller ◽  
...  
Keyword(s):  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Sub Saharan Africa ◽  
Type I ◽  
Rat Strains ◽  
Valley Fever ◽  
Inbred Rat Strains ◽  
Inbred Rat

Rift Valley fever virus (RVFV) is the causative agent of Rift Valley fever, a widespread disease of domestic animals and humans in sub-Saharan Africa. Laboratory rats have frequently been used as an animal model for studying the pathogenesis of Rift Valley fever. It is shown here that Lewis rats (LEW/mol) are susceptible to infection with RVFV, whereas Wistar–Furth (WF/mol) rats are resistant to RVFV infection. LEW/mol rats developed acute hepatitis and died after infection with RVFV strain ZH548, whereas WF/mol rats survived the infection. Cross-breeding of resistant WF/mol rats with susceptible LEW/mol rats demonstrated that resistance is segregated as a single dominant gene. Primary hepatocytes but not glial cells from WF/mol rats showed the resistant phenotype in cell culture, indicating that resistance was cell type-specific. Moreover, when cultured hepatocytes were stimulated with interferon (IFN) type I there was no indication of a regulatory role of IFN in the RVFV-resistance gene expression in WF/mol rats. Interestingly, previous reports have shown that LEW rats from a different breeding stock (LEW/mai) are resistant to RVFV infections, whereas WF/mai rats are susceptible. Thus, inbred rat strains seem to differ in virus susceptibility depending on their breeding histories. A better genetic characterization of inbred rat strains and a revision in nomenclature is needed to improve animal experimentation in the future.

scholarly journals Isotype-Specific Fc Effector Functions Enhance Antibody-Mediated Rift Valley Fever Virus Protection In Vivo

mSphere ◽  
2021 ◽  
Author(s):  
Haley N. Cartwright ◽  
Dominique J. Barbeau ◽  
Anita K. McElroy
Keyword(s):  
Middle East ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Disease Burden ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Valley Fever ◽  
Effector Functions

Rift Valley fever virus (RVFV) is a mosquito-borne virus found throughout Africa and into the Middle East. It has a substantial disease burden; in areas of endemicity, up to 60% of adults are seropositive.

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