title: Shedding of Ebola Virus Surface Glycoprotein Is a Mechanism of Self-regulation of Cellular Cytotoxicity and Has a Direct Effect on Virus Infectivity.
abstract: The surface glycoprotein (GP) is responsible for Ebola virus (EBOV) attachment and membrane fusion during virus entry. Surface expression of highly glycosylated GP causes marked cytotoxicity via masking of a wide range of cellular surface molecules, including integrins. Considerable amounts of surface GP are shed from virus-infected cells in a soluble truncated form by tumor necrosis factor α-converting enzyme. In this study, the role of GP shedding was investigated using a reverse genetics approach by comparing recombinant viruses possessing amino acid substitutions at the GP shedding site. Virus with an L635V substitution showed a substantial decrease in shedding, whereas a D637V substitution resulted in a striking increase in the release of shed GP. Variations in shedding efficacy correlated with observed differences in the amounts of shed GP in the medium, GP present in virus-infected cells, and GP present on virions. An increase in shedding appeared to be associated with a reduction in viral cytotoxicity, and, vice versa, the virus that shed less was more cytotoxic. An increase in shedding also resulted in a reduction in viral infectivity, whereas a decrease in shedding efficacy enhanced viral growth characteristics in vitro. Differences in shedding efficacy and, as a result, differences in the amount of mature GP available for incorporation into budding virions did not equate to differences in overall release of viral particles. Likewise, data suggest that the resulting differences in the amount of mature GP on the cell surface led to variations in the GP content of released particles and, as a consequence, in infectivity. In conclusion, fine-tuning of the levels of EBOV GP expressed at the surface of virus-infected cells via GP shedding plays an important role in EBOV replication by orchestrating the balance between optimal virion GP content and cytotoxicity caused by GP.
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111 - CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, France Institut für Virologie, Philipps-Universität Marburg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Dolnik
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111 - CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, France.
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Volchkova
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111 - CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, France.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Escudero-Perez
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111 - CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, France.
authors.forename: Philip
authors.initials: P
authors.lastname: Lawrence
authors.affiliation: Institut für Virologie, Philipps-Universität Marburg, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Klenk
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111 - CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, France.
authors.forename: Viktor E
authors.initials: VE
authors.lastname: Volchkov
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D029043:Ebolavirus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D019142:Hemorrhagic Fever, Ebola / Q000821:virology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D014774:Virulence / Q000235:genetics; D053586:Virus Internalization; D014779:Virus Replication / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins; D014764:Viral Proteins
keywords: Ebola; Ebolavirus; cytotoxicity; glycoprotein GP; infectivity; shed GP; shedding