Lethal mutagenesis of Rift Valley fever virus induced by favipiravir

ABSTRACTRift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks paying a considerable toll of human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic and emerging RNA virus infections of humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies, and a decrease of specific infectivity, hallmarks of lethal mutagenesis.

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Lethal Mutagenesis of Rift Valley Fever Virus Induced by Favipiravir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00669-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 7

Author(s):

Belén Borrego ◽

Ana I. de Ávila ◽

Esteban Domingo ◽

Alejandro Brun

Keyword(s):

Animal Models ◽

Cell Cultures ◽

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Nucleotide Sequence Analysis ◽

African Countries ◽

Valley Fever ◽

Lethal Mutagenesis

ABSTRACT Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic, and emerging RNA virus infections in humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work, we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies and a decrease of specific infectivity, hallmarks of lethal mutagenesis.

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Animal models of Rift Valley fever virus infection

Virus Research ◽

10.1016/j.virusres.2011.10.023 ◽

2012 ◽

Vol 163 (2) ◽

pp. 417-423 ◽

Cited By ~ 28

Author(s):

Ted M. Ross ◽

Nitin Bhardwaj ◽

Stephanie J. Bissel ◽

Amy L. Hartman ◽

Darci R. Smith

Keyword(s):

Animal Models ◽

Virus Infection ◽

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Valley Fever

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Evaluation of Factors Related to Growth of Rift Valley Fever Virus in Suspended Cell Cultures

10.21236/ad0850080 ◽

1969 ◽

Author(s):

Jerry S. Walker ◽

Richard C. Carter ◽

Frederick Klein ◽

Shirley E. Snowden ◽

Ralph E. Lincoln

Keyword(s):

Cell Cultures ◽

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Suspended Cell ◽

Valley Fever

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Morphology and development of Rift Valley fever virus in vero cell cultures

Journal of Medical Virology ◽

10.1002/jmv.1890240205 ◽

1988 ◽

Vol 24 (2) ◽

pp. 161-174 ◽

Cited By ~ 27

Author(s):

D. S. Ellis ◽

P. V. Shirodaria ◽

Elizabeth Fleming ◽

D. I. H. Simpson

Keyword(s):

Vero Cell ◽

Cell Cultures ◽

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Valley Fever

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Evaluation of Factors Related to Growth of Rift Valley Fever Virus in Suspended Cell Cultures

Applied Microbiology ◽

10.1128/aem.17.5.658-664.1969 ◽

1969 ◽

Vol 17 (5) ◽

pp. 658-664 ◽

Cited By ~ 3

Author(s):

Jerry S. Walker ◽

Richard C. Carter ◽

Frederick Klein ◽

Shirley E. Snowden ◽

Ralph E. Lincoln

Keyword(s):

Cell Cultures ◽

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Suspended Cell ◽

Valley Fever

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Reproducing the Rift Valley fever virus mosquito-lamb-mosquito transmission cycle

Scientific Reports ◽

10.1038/s41598-020-79267-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Paul J. Wichgers Schreur ◽

Rianka P. M. Vloet ◽

Jet Kant ◽

Lucien van Keulen ◽

Jose L. Gonzales ◽

...

Keyword(s):

Animal Models ◽

Rift Valley ◽

Rift Valley Fever ◽

Rift Valley Fever Virus ◽

Vector Competence ◽

Mosquito Species ◽

Fever Virus ◽

Valley Fever ◽

Transmission Cycle ◽

Membrane Feeding

AbstractRift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that is pathogenic to ruminants and humans. The virus is endemic to Africa and the Arabian Peninsula where outbreaks are characterized by abortion storms and mortality of newborns, particularly in sheep herds. Vector competence experiments in laboratory settings have suggested that over 50 mosquito species are capable of transmitting RVFV. Transmission of mosquito-borne viruses in the field is however influenced by numerous factors, including population densities, blood feeding behavior, extrinsic incubation period, longevity of vectors, and viremia levels in vertebrate hosts. Animal models to study these important aspects of RVFV transmission are currently lacking. In the present work, RVFV was transmitted to European (Texel-swifter cross-breed) lambs by laboratory-reared Aedes aegypti mosquitoes that were infected either by membrane feeding on a virus-spiked blood meal or by feeding on lambs that developed viremia after intravenous inoculation of RVFV. Feeding of mosquitoes on viremic lambs resulted in strikingly higher infection rates as compared to membrane feeding. Subsequent transmission of RVFV from lamb to lamb by infected mosquitoes was highly efficient in both models. The animal models described here can be used to study mosquito-mediated transmission of RVFV among the major natural target species and to evaluate the efficacy of vaccines against mosquito-mediated RVFV infection.

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Pathogenesis of Rift Valley Fever Virus Aerosol Infection in STAT2 Knockout Hamsters

Viruses ◽

10.3390/v10110651 ◽

2018 ◽

Vol 10 (11) ◽

pp. 651 ◽

Cited By ~ 1

Author(s):

Brady Hickerson ◽

Jonna Westover ◽

Arnaud Van Wettere ◽

Johanna Rigas ◽

Jinxin Miao ◽

...

Keyword(s):

Animal Models ◽

Rift Valley ◽

Rift Valley Fever ◽

Vaccine Development ◽

Rift Valley Fever Virus ◽

Fever Virus ◽

Infection Model ◽

Valley Fever ◽

Cell Parameters ◽

Aerosol Exposure

Rift Valley fever virus (RVFV) is an emerging pathogen capable of causing severe disease in livestock and humans and can be transmitted by multiple routes including aerosol exposure. Several animal models have been developed to gain insight into the pathogenesis associated with aerosolized RVFV infection, but work with these models is restricted to high containment biosafety level (BSL) laboratories limiting their use for antiviral and vaccine development studies. Here, we report on a new RVFV inhalation infection model in STAT2 KO hamsters exposed to aerosolized MP-12 vaccine virus by nose-only inhalation that enables a more accurate delivery and measurement of exposure dose. RVFV was detected in hepatic and other tissues 4–5 days after challenge, consistent with virus-induced lesions in the liver, spleen and lung. Furthermore, assessment of blood chemistry and hematological parameters revealed alterations in several liver disease markers and white blood cell parameters. Our results indicate that STAT2 KO hamsters develop a disease course that shares features of disease observed in human cases and in other animal models of RVFV aerosol exposure, supporting the use of this BSL-2 infection model for countermeasure development efforts.

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