2. Academic Validation
  3. A Diacylglycerol Kinase Inhibitor, R-59-022, Blocks Filovirus Internalization in Host Cells

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

Affiliations

  • 1 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. cwark095@uottawa.ca.
  • 2 Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. cwark095@uottawa.ca.
  • 3 Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. cwark095@uottawa.ca.
  • 4 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. sdori068@uottawa.ca.
  • 5 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. motte017@uottawa.ca.
  • 6 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. nlebl062@uottawa.ca.
  • 7 Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. nlebl062@uottawa.ca.
  • 8 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. tsmit121@uottawa.ca.
  • 9 Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. tsmit121@uottawa.ca.
  • 10 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. sqiu096@uottawa.ca.
  • 11 Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. sqiu096@uottawa.ca.
  • 12 Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. sqiu096@uottawa.ca.
  • 13 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. morgan.fullerton@uottawa.ca.
  • 14 Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. morgan.fullerton@uottawa.ca.
  • 15 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada. darwyn.kobasa@canada.ca.
  • 16 Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. darwyn.kobasa@canada.ca.
  • 17 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. marceline.cote@uottawa.ca.
  • 18 Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. marceline.cote@uottawa.ca.
  • 19 Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada. marceline.cote@uottawa.ca.
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.

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