Abstract
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.
Highlights
Since its first discovery in 1976, Ebola virus (EBOV) has been responsible for 18 outbreaks with case fatality rates (CFR) ranging from 25–88% [1]
To generate mouse-adapted EBOV/Makona-MA, we started with the wild-type EBOV/Makona genome and inserted a subset of the mutations identified in EBOV/Mayinga-MA that contribute towards virulence [30]
We inserted into the EBOV/Makona genome the following seven mutations that were identified in EBOV/Mayinga-MA: NP (S72G), GP (S65P, S246P), VP24 (+A in non-coding regions (NCR), T50I), and L (F934L, I1532V)
Summary
Since its first discovery in 1976, Ebola virus (EBOV) has been responsible for 18 outbreaks with case fatality rates (CFR) ranging from 25–88% [1]. From 2013 to 2016, the largest Ebola virus epidemic in history occurred in West Africa resulting in over 28,000 confirmed cases and more than 11,000 deaths [2]. This outbreak originated in Guinea and within half a year, the virus quickly spread to the capitals of neighbouring countries (Liberia and Sierra Leone) and later, worldwide as a consequence of imported travel-related cases [3]. Despite the resolution of the West African outbreak, the risk of future EBOV outbreaks continues to be a concern. This is exemplified by the ongoing outbreak that is occurring in the Democratic
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