Ebola virus triggers receptor tyrosine kinase-dependent signaling to promote the delivery of viral particles to entry-conducive intracellular compartments

• DOI: 10.1371/journal.ppat.1009275
• Publication Date: 2021-01-29T18:43:13Z
• Authors: Corina M. Stewart; Alexandra Phan; Yuxia Bo; Nicholas D. LeBlond; Tyler K. T. Smith; Geneviève Laroche; Patrick M. Giguère; Morgan D. Fullerton; Martin Pelchat; Darwyn Kobasa; Marceline Côté
• Keywords: Host factors; Entry inhibitor

Filoviruses, such as the Ebola virus (EBOV) and Marburg (MARV), are causative agents of sporadic outbreaks hemorrhagic fevers in humans. To infect cells, filoviruses internalized via macropinocytosis traffic through endosomal pathway where host cathepsin-dependent cleavage viral glycoproteins occurs. Subsequently, cleaved glycoprotein interacts with late endosome/lysosome resident protein, Niemann-Pick C1 (NPC1). This interaction is hypothesized to trigger membrane fusion, which results delivery genome into cytoplasm subsequent initiation replication. Some studies suggest that EBOV particles activate signaling cascades host-trafficking factors promote their localization essential for entry. However, mechanism these activating signals initiated remains unknown. By screening a kinase inhibitor library, we found receptor tyrosine inhibitors potently block MARV GP-dependent Inhibitors epidermal growth factor (EGFR), protein Met (c-Met), insulin (InsR)/insulin like 1 (IGF1R) blocked filoviral GP-mediated entry prevented replicative Vero cells. Furthermore, c-Met InsR/IGF1R also macrophages, primary targets infection. Interestingly, while interfered trafficking NPC1, was not impaired presence EGFR inhibitor. Instead, observed NPC1 positive compartments were phenotypically altered rendered incompetent permit Despite different mechanisms action, all three RTK tested inhibited virus-induced Akt activation, providing possible explanation how may pathways during In sum, strongly kinases initiate efficient post-internalization steps.