title: Cell adhesion-dependent membrane trafficking of a binding partner for the ebolavirus glycoprotein is a determinant of viral entry.
abstract: Ebolavirus is a hemorrhagic fever virus associated with high mortality. Although much has been learned about the viral lifecycle and pathogenesis, many questions remain about virus entry. We recently showed that binding of the receptor binding region (RBR) of the ebolavirus glycoprotein (GP) and infection by GP pseudovirions increase on cell adhesion independently of mRNA or protein synthesis. One model to explain these observations is that, on cell adhesion, an RBR binding partner translocates from an intracellular vesicle to the cell surface. Here, we provide evidence for this model by showing that suspension 293F cells contain an RBR binding site within a membrane-bound compartment associated with the trans-Golgi network and microtubule-organizing center. Consistently, trafficking of the RBR binding partner to the cell surface depends on microtubules, and the RBR binding partner is internalized when adherent cells are placed in suspension. Based on these observations, we reexamined the claim that lymphocytes, which are critical for ebolavirus pathogenesis, are refractory to infection because they lack an RBR binding partner. We found that both cultured and primary human lymphocytes (in suspension) contain an intracellular pool of an RBR binding partner. Moreover, we identified two adherent primate lymphocytic cell lines that bind RBR at their surface and strikingly, support GP-mediated entry and infection. In summary, our results reveal a mode of determining viral entry by a membrane-trafficking event that translocates an RBR binding partner to the cell surface, and they suggest that this process may be operative in cells important for ebolavirus pathogenesis (e.g., lymphocytes and macrophages).
authors.affiliation: Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Dube
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schornberg
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Shoemaker
authors.forename: Sue E
authors.initials: SE
authors.lastname: Delos
authors.forename: Tzanko S
authors.initials: TS
authors.lastname: Stantchev
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Clouse
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Broder
authors.forename: Judith M
authors.initials: JM
authors.lastname: White
mesh_terms: D001402:B-Lymphocytes / Q000502:physiology / Q000821:virology; D001665:Binding Sites; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology / Q000821:virology; D029043:Ebolavirus / Q000472:pathogenicity* / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells; D008214:Lymphocytes / Q000502:physiology* / Q000821:virology*; D008869:Microtubule-Associated Proteins / Q000502:physiology; D010940:Plant Proteins / Q000502:physiology; D011991:Receptors, Virus / Q000502:physiology; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000502:physiology*; D053586:Virus Internalization; D021601:trans-Golgi Network / Q000502:physiology
chemical_list: D008869:Microtubule-Associated Proteins; D010940:Plant Proteins; D011991:Receptors, Virus; D014759:Viral Envelope Proteins; C113189:envelope glycoprotein, Ebola virus; C119741:microtububle assembly protein 49, Nicotiana tabacum
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