A Diacylglycerol Kinase Inhibitor, R-59-022, Blocks Filovirus Internalization in Host Cells

  • Viruses. 2019 Mar 1;11(3):206. doi: 10.3390/v11030206.
Corina M Stewart  1  2  3 ,  Stephanie S Dorion  4 ,  Marie A F Ottenbrite  5 ,  Nicholas D LeBlond  6  7 ,  Tyler K T Smith  8  9 ,  Shirley Qiu  10  11  12 ,  Morgan D Fullerton  13  14 ,  Darwyn Kobasa  15  16 ,  Marceline Côté  17  18  19
Affiliations
  • 1. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 2. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 3. Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 4. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 5. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 6. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 7. Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 8. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 9. Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 10. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 11. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 12. Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 13. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 14. Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 15. Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada. [email protected].
  • 16. Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. [email protected].
  • 17. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 18. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
  • 19. Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. [email protected].
PMID: 30832223 DOI: 10.3390/v11030206
Abstract

Filoviruses, such as Ebola virus (EBOV) and Marburg virus, are causative agents of unpredictable outbreaks of severe hemorrhagic fevers in humans and non-human primates. For Infection, filoviral particles need to be internalized and delivered to intracellular vesicles containing Cathepsin proteases and the viral receptor Niemann-Pick C1. Previous studies have shown that EBOV triggers macropinocytosis of the viral particles in a glycoprotein (GP)-dependent manner, but the molecular events required for Filovirus internalization remain mostly unknown. Here we report that the diacylglycerol kinase inhibitor, R-59-022, blocks EBOV GP-mediated entry into Vero cells and bone marrow-derived macrophages. Investigation of the mode of action of the inhibitor revealed that it blocked an early step in entry, more specifically, the internalization of the viral particles via macropinocytosis. Finally, R-59-022 blocked viral entry mediated by a panel of pathogenic Filovirus GPs and inhibited growth of replicative Ebola virus. Taken together, our studies suggest that R-59-022 could be used as a tool to investigate macropinocytic uptake of filoviruses and could be a starting point for the development of pan-filoviral therapeutics.

Keywords
Ebola virus; Marburg virus; diacylglycerol kinase; filoviruses; macropinocytosis; viral entry.
Products