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Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus

Ebola virus (EBOV) is a zoonotic pathogen that poses a significant threat to public health, causing sporadic yet devastating outbreaks that have the potential to spread worldwide, as demonstrated during the 2013–2016 West African outbreak. Mouse models of infection are important tools for the develo...

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Autores principales: Chan, Mable, Leung, Anders, Griffin, Bryan D., Vendramelli, Robert, Tailor, Nikesh, Tierney, Kevin, Audet, Jonathan, Kobasa, Darwyn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893688/
https://www.ncbi.nlm.nih.gov/pubmed/31717793
http://dx.doi.org/10.3390/v11110987
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author Chan, Mable
Leung, Anders
Griffin, Bryan D.
Vendramelli, Robert
Tailor, Nikesh
Tierney, Kevin
Audet, Jonathan
Kobasa, Darwyn
author_facet Chan, Mable
Leung, Anders
Griffin, Bryan D.
Vendramelli, Robert
Tailor, Nikesh
Tierney, Kevin
Audet, Jonathan
Kobasa, Darwyn
author_sort Chan, Mable
collection PubMed
description Ebola virus (EBOV) is a zoonotic pathogen that poses a significant threat to public health, causing sporadic yet devastating outbreaks that have the potential to spread worldwide, as demonstrated during the 2013–2016 West African outbreak. Mouse models of infection are important tools for the development of therapeutics and vaccines. Exposure of immunocompetent mice to clinical isolates of EBOV is nonlethal; consequently, EBOV requires prior adaptation in mice to cause lethal disease. Until now, the only immunocompetent EBOV mouse model was based on the Mayinga variant, which was isolated in 1976. Here, we generated a novel mouse-adapted (MA)-EBOV based on the 2014 Makona isolate by inserting EBOV/Mayinga-MA mutations into the EBOV/Makona genome, followed by serial passaging of the rescued virus in suckling mice. The resulting EBOV/Makona-MA causes lethal disease in adult immunocompetent mice within 6 to 9 days and has a lethal dose (LD50) of 0.004 plaque forming units (PFU). Two additional mutations emerged after mouse-adaptation in the viral nucleoprotein (NP) and membrane-associated protein VP24. Using reverse genetics, we found the VP24 mutation to be critical for EBOV/Makona-MA virulence. EBOV/Makona-MA infected mice that presented with viremia, high viral burden in organs, increased release of pro-inflammatory cytokines/chemokines, and lymphopenia. Our mouse model will help advance pre-clinical development of countermeasures against contemporary EBOV variants.
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spelling pubmed-68936882019-12-23 Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus Chan, Mable Leung, Anders Griffin, Bryan D. Vendramelli, Robert Tailor, Nikesh Tierney, Kevin Audet, Jonathan Kobasa, Darwyn Viruses Article Ebola virus (EBOV) is a zoonotic pathogen that poses a significant threat to public health, causing sporadic yet devastating outbreaks that have the potential to spread worldwide, as demonstrated during the 2013–2016 West African outbreak. Mouse models of infection are important tools for the development of therapeutics and vaccines. Exposure of immunocompetent mice to clinical isolates of EBOV is nonlethal; consequently, EBOV requires prior adaptation in mice to cause lethal disease. Until now, the only immunocompetent EBOV mouse model was based on the Mayinga variant, which was isolated in 1976. Here, we generated a novel mouse-adapted (MA)-EBOV based on the 2014 Makona isolate by inserting EBOV/Mayinga-MA mutations into the EBOV/Makona genome, followed by serial passaging of the rescued virus in suckling mice. The resulting EBOV/Makona-MA causes lethal disease in adult immunocompetent mice within 6 to 9 days and has a lethal dose (LD50) of 0.004 plaque forming units (PFU). Two additional mutations emerged after mouse-adaptation in the viral nucleoprotein (NP) and membrane-associated protein VP24. Using reverse genetics, we found the VP24 mutation to be critical for EBOV/Makona-MA virulence. EBOV/Makona-MA infected mice that presented with viremia, high viral burden in organs, increased release of pro-inflammatory cytokines/chemokines, and lymphopenia. Our mouse model will help advance pre-clinical development of countermeasures against contemporary EBOV variants. MDPI 2019-10-26 /pmc/articles/PMC6893688/ /pubmed/31717793 http://dx.doi.org/10.3390/v11110987 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chan, Mable
Leung, Anders
Griffin, Bryan D.
Vendramelli, Robert
Tailor, Nikesh
Tierney, Kevin
Audet, Jonathan
Kobasa, Darwyn
Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus
title Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus
title_full Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus
title_fullStr Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus
title_full_unstemmed Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus
title_short Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus
title_sort generation and characterization of a mouse-adapted makona variant of ebola virus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893688/
https://www.ncbi.nlm.nih.gov/pubmed/31717793
http://dx.doi.org/10.3390/v11110987
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