Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir.

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.

• Authors: Jason E Comer, Olivier Escaffre, Natasha Neef, Trevor Brasel, Terry L Juelich, Jennifer K Smith, Jeanon Smith, Birte Kalveram, David D Perez, Shane Massey, Lihong Zhang, Alexander N Freiberg
• Journal: Viruses (Viruses) Vol. 11 Issue 2 (02 03 2019) ISSN: 1999-4915 [Electronic] Switzerland
• PMID: 30717492 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amides
• Antiviral Agents
• Pyrazines
• RNA, Viral
• Receptors, Interferon
• favipiravir

Topics

• Amides (therapeutic use)
• Animals
• Antiviral Agents (therapeutic use)
• Disease Models, Animal
• Ebolavirus
• Female
• Filoviridae
• Filoviridae Infections (drug therapy)
• Gene Knockout Techniques
• Hemorrhagic Fever, Ebola (drug therapy)
• Liver (pathology)
• Male
• Marburg Virus Disease (drug therapy)
• Marburgvirus
• Mice
• Mice, Knockout
• Proof of Concept Study
• Pyrazines (therapeutic use)
• RNA, Viral (blood)
• Receptors, Interferon (genetics, immunology)
• Spleen (pathology)
• Virulence