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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-10-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/11/11/987 |
| _version_ | 1818852041897803776 |
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| author | Mable Chan Anders Leung Bryan D. Griffin Robert Vendramelli Nikesh Tailor Kevin Tierney Jonathan Audet Darwyn Kobasa |
| author_facet | Mable Chan Anders Leung Bryan D. Griffin Robert Vendramelli Nikesh Tailor Kevin Tierney Jonathan Audet Darwyn Kobasa |
| author_sort | Mable Chan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T07:14:37Z |
| format | Article |
| id | doaj.art-3042aa38bef34edfa1ba009432a7e529 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-12-19T07:14:37Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-3042aa38bef34edfa1ba009432a7e5292022-12-21T20:31:07ZengMDPI AGViruses1999-49152019-10-01111198710.3390/v11110987v11110987Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola VirusMable Chan0Anders Leung1Bryan D. Griffin2Robert Vendramelli3Nikesh Tailor4Kevin Tierney5Jonathan Audet6Darwyn Kobasa7Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, CanadaSpecial Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, CanadaSpecial Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, CanadaSpecial Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, CanadaSpecial Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, CanadaSpecial Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, CanadaSpecial Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, CanadaSpecial Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, R3E 3R2, CanadaEbola 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.https://www.mdpi.com/1999-4915/11/11/987ebola virusmakonamayingamouse-adaptedanimal modelmicereverse geneticspathogenesisvp24 |
| spellingShingle | Mable Chan Anders Leung Bryan D. Griffin Robert Vendramelli Nikesh Tailor Kevin Tierney Jonathan Audet Darwyn Kobasa Generation and Characterization of a Mouse-Adapted Makona Variant of Ebola Virus Viruses ebola virus makona mayinga mouse-adapted animal model mice reverse genetics pathogenesis vp24 |
| 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 | ebola virus makona mayinga mouse-adapted animal model mice reverse genetics pathogenesis vp24 |
| url | https://www.mdpi.com/1999-4915/11/11/987 |
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