Identification of Single Amino Acid Changes in the Rift Valley Fever Virus Polymerase Core Domain Contributing to Virus Attenuation In Vivo
Author
Borrego, Belén
Moreno, Sandra
López-Valiñas, Álvaro
de la Losa, Nuria
Weber, Friedemann
Núñez, José Ignacio
Brun, Alejandro
Publication date
2022-04-28ISSN
2235-2988
Abstract
Rift Valley fever (RVF) is an arboviral zoonotic disease affecting many African countries with
the potential to spread to other geographical areas. RVF affects sheep, goats, cattle and
camels, causing a high rate of abortions and death of newborn lambs. Also, humans can
be infected, developing a usually self-limiting disease that can turn into a more severe
illness in a low percentage of cases. Although different veterinary vaccines are available in
endemic areas in Africa, to date no human vaccine has been licensed. In previous works,
we described the selection and characterization of a favipiravir-mutagenized RVFV variant,
termed 40Fp8, with potential as a RVF vaccine candidate due to the strong attenuation
shown in immunocompromised animal models. Compared to the parental South African
56/74 viral strain, 40Fp8 displayed 7 amino acid substitutions in the L-protein, three of
them located in the central region corresponding to the catalytic core of the RNAdependent RNA polymerase (RdRp). In this work, by means of a reverse genetics system,
we have analyzed the effect on virulence of these amino acid changes, alone or combined,
both in vitro and in vivo. We found that the simultaneous introduction of two changes
(G924S and A1303T) in the heterologous ZH548-RVFV Egyptian strain conferred
attenuated phenotypes to the rescued viruses as shown in infected mice without
affecting virus immunogenicity. Our results suggest that both changes induce
resistance to favipiravir likely associated to some fitness cost that could be the basis for
the observed attenuation in vivo. Conversely, the third change, I1050V, appears to be a
compensatory mutation increasing viral fitness. Altogether, these results provide relevant
information for the safety improvement of novel live attenuated RVFV vaccines.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
619 - Veterinary science
Pages
16
Publisher
Frontiers Media
Is part of
Frontiers in Cellular and Infection Microbiology
Citation
Borrego, Belén, Sandra Moreno, Álvaro López-Valiñas, Nuria de la Losa, Friedemann Weber, José Ignacio Núñez, and Alejandro Brun. 2022. "Identification Of Single Amino Acid Changes In The Rift Valley Fever Virus Polymerase Core Domain Contributing To Virus Attenuation In Vivo". Frontiers In Cellular And Infection Microbiology 12. doi:10.3389/fcimb.2022.875539.
Grant agreement number
INIA-FEDER/Programa Estatal de I+D+I orientada a los retos de la sociedad/AGL2017-83226-R/ES/UTILIZACION DEL VIRUS DE LA FIEBRE DEL VALLE DEL RIFT COMO VECTOR VACUNAL: MEJORA RACIONAL DE SU SEGURIDAD, ESTABILIDAD Y TRAZABILIDAD/
INIA-FEDER/Programa Estatal de I+D+I orientada a los retos de la sociedad/PdC2021-121717-I00/ES/ /
Program
Sanitat Animal
This item appears in the following Collection(s)
- ARTICLES CIENTÍFICS [2685]
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/