Abstract
The 2014 Ebolavirus outbreak in West Africa highlighted the need for vaccines and therapeutics to prevent and treat filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would facilitate the screening of anti-filovirus agents. To that end, we characterized knockout mice lacking α/β and γ interferon receptors (IFNAGR KO) as a model for wild-type filovirus infection. Intraperitoneal challenge of IFNAGR KO mice with several known human pathogenic species from the genus Ebolavirus and Marburgvirus, except Bundibugyo ebolavirus and Taï Forest ebolavirus, caused variable mortality rate. Further characterization of the prototype Ebola virus Kikwit isolate infection in this KO mouse model showed 100% lethality down to a dilution equivalent to 1.0 × 10−1 pfu with all deaths occurring between 7 and 9 days post-challenge. Viral RNA was detectable in serum after challenge with 1.0 × 102 pfu as early as one day after infection. Changes in hematology and serum chemistry became pronounced as the disease progressed and mirrored the histological changes in the spleen and liver that were also consistent with those described for patients with Ebola virus disease. In a proof-of-principle study, treatment of Ebola virus infected IFNAGR KO mice with favipiravir resulted in 83% protection. Taken together, the data suggest that IFNAGR KO mice may be a useful model for early screening of anti-filovirus medical countermeasures.
Highlights
Filoviruses are non-segmented, negative-sense RNA viruses responsible for causing several outbreaks of hemorrhagic fever throughout Africa
All mice challenged with Bundibugyo virus (BDBV) or Taï Forest virus (TAFV) survived to the end of the study at 21 days post infection
All mice challenged with BDBV or TAFV survived to of the study without any significant weight loss (Figure 1A,B), even though BDBV-challenged the end of the study without any significant weight loss (Figure 1A,B), even though BDBV-challenged animals temporarily exhibited clinical scores of 2 on days 5 and 6
Summary
Filoviruses (family Filoviridae) are non-segmented, negative-sense RNA viruses responsible for causing several outbreaks of hemorrhagic fever throughout Africa. Five species are classified in the genus level of Ebolavirus, including Zaire ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus, Viruses 2019, 11, 137; doi:10.3390/v11020137 www.mdpi.com/journal/viruses. Marburg Marburgvirus is the only known species of genus. Marburgvirus [1] and only include Marburg and Ravn virus. Ebola virus (EBOV) and Marburg virus (MARV) are associated with high fatality rates ranging from 25% to 90% [2,3,4]. Bundibugyo virus (BDBV), cause severe disease but have so far been responsible for fewer and smaller outbreaks. Taï Forest virus (TAFV) has only caused a single known case, which did not result in fatality and Reston virus (RESTV), and is deemed nonpathogenic for humans [5,6]. The disease usually presents with flu-like symptoms accompanied by gastro-intestinal symptoms and as it progresses maculo-papulary rash, petichae, conjunctival hemorrhage, epistaxis, melena, hematemesis, shock, and encephalopathy can develop [8]
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