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Favipiravir (T-705) Protects IFNAR(−/−) Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner

Zika virus (ZIKV), a member of the Flaviviridae family, is an important human pathogen that has caused epidemics in Africa, Southeast Asia, and the Americas. No licensed treatments for ZIKV disease are currently available. Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) and ribavirin (...

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Autores principales: Matz, Keesha, Emanuel, Jackson, Callison, Julie, Gardner, Don, Rosenke, Rebecca, Mercado-Hernandez, Reinaldo, Williamson, Brandi N., Feldmann, Heinz, Marzi, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227069/
https://www.ncbi.nlm.nih.gov/pubmed/34072604
http://dx.doi.org/10.3390/microorganisms9061178
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author Matz, Keesha
Emanuel, Jackson
Callison, Julie
Gardner, Don
Rosenke, Rebecca
Mercado-Hernandez, Reinaldo
Williamson, Brandi N.
Feldmann, Heinz
Marzi, Andrea
author_facet Matz, Keesha
Emanuel, Jackson
Callison, Julie
Gardner, Don
Rosenke, Rebecca
Mercado-Hernandez, Reinaldo
Williamson, Brandi N.
Feldmann, Heinz
Marzi, Andrea
author_sort Matz, Keesha
collection PubMed
description Zika virus (ZIKV), a member of the Flaviviridae family, is an important human pathogen that has caused epidemics in Africa, Southeast Asia, and the Americas. No licensed treatments for ZIKV disease are currently available. Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) and ribavirin (1-(β-D-Ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide) are nucleoside analogs that have exhibited antiviral activity against a broad spectrum of RNA viruses, including some flaviviruses. In this study, we strengthened evidence for favipiravir and ribavirin inhibition of ZIKV replication in vitro. Testing in IFNAR(−/−) mice revealed that daily treatments of favipiravir were sufficient to provide protection against lethal ZIKV challenge in a dose-dependent manner but did not completely abrogate disease. Ribavirin, on the other hand, had no beneficial effect against ZIKV infection in this model and under the conditions examined. Combined treatment of ribavirin and favipiravir did not show improved outcomes over ribavirin alone. Surprisingly, outcome of favipiravir treatment was sex-dependent, with 87% of female but only 25% of male mice surviving lethal ZIKV infection. Since virus mutations were not associated with outcome, a sex-specific host response likely explains the observed sex difference.
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spelling pubmed-82270692021-06-26 Favipiravir (T-705) Protects IFNAR(−/−) Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner Matz, Keesha Emanuel, Jackson Callison, Julie Gardner, Don Rosenke, Rebecca Mercado-Hernandez, Reinaldo Williamson, Brandi N. Feldmann, Heinz Marzi, Andrea Microorganisms Article Zika virus (ZIKV), a member of the Flaviviridae family, is an important human pathogen that has caused epidemics in Africa, Southeast Asia, and the Americas. No licensed treatments for ZIKV disease are currently available. Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) and ribavirin (1-(β-D-Ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide) are nucleoside analogs that have exhibited antiviral activity against a broad spectrum of RNA viruses, including some flaviviruses. In this study, we strengthened evidence for favipiravir and ribavirin inhibition of ZIKV replication in vitro. Testing in IFNAR(−/−) mice revealed that daily treatments of favipiravir were sufficient to provide protection against lethal ZIKV challenge in a dose-dependent manner but did not completely abrogate disease. Ribavirin, on the other hand, had no beneficial effect against ZIKV infection in this model and under the conditions examined. Combined treatment of ribavirin and favipiravir did not show improved outcomes over ribavirin alone. Surprisingly, outcome of favipiravir treatment was sex-dependent, with 87% of female but only 25% of male mice surviving lethal ZIKV infection. Since virus mutations were not associated with outcome, a sex-specific host response likely explains the observed sex difference. MDPI 2021-05-29 /pmc/articles/PMC8227069/ /pubmed/34072604 http://dx.doi.org/10.3390/microorganisms9061178 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Matz, Keesha
Emanuel, Jackson
Callison, Julie
Gardner, Don
Rosenke, Rebecca
Mercado-Hernandez, Reinaldo
Williamson, Brandi N.
Feldmann, Heinz
Marzi, Andrea
Favipiravir (T-705) Protects IFNAR(−/−) Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner
title Favipiravir (T-705) Protects IFNAR(−/−) Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner
title_full Favipiravir (T-705) Protects IFNAR(−/−) Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner
title_fullStr Favipiravir (T-705) Protects IFNAR(−/−) Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner
title_full_unstemmed Favipiravir (T-705) Protects IFNAR(−/−) Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner
title_short Favipiravir (T-705) Protects IFNAR(−/−) Mice against Lethal Zika Virus Infection in a Sex-Dependent Manner
title_sort favipiravir (t-705) protects ifnar(−/−) mice against lethal zika virus infection in a sex-dependent manner
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227069/
https://www.ncbi.nlm.nih.gov/pubmed/34072604
http://dx.doi.org/10.3390/microorganisms9061178
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