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Open AccessArticle

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

1
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, Canada
2
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB, R3E 0J9, Canada
*
Author to whom correspondence should be addressed.
Viruses 2019, 11(11), 987; https://doi.org/10.3390/v11110987
Received: 15 September 2019 / Revised: 12 October 2019 / Accepted: 23 October 2019 / Published: 26 October 2019
(This article belongs to the Special Issue Pathogenesis of Emerging Viral Infections)
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. View Full-Text
Keywords: Ebola virus; Makona; Mayinga; mouse-adapted; animal model; mice; reverse genetics; pathogenesis; VP24 Ebola virus; Makona; Mayinga; mouse-adapted; animal model; mice; reverse genetics; pathogenesis; VP24
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Chan, M.; Leung, A.; Griffin, B.D.; Vendramelli, R.; Tailor, N.; Tierney, K.; Audet, J.; Kobasa, D. Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus. Viruses 2019, 11, 987.

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