Characterization of the filovirus-resistant cell line SH-SY5Y reveals redundant role of cell surface entry factors

  • Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann–Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, earlier steps of filoviral infection remain poorly characterized. Numerous plasma membrane proteins have been implicated in attachment but it is still unclear which ones are sufficient for productive entry. To define a minimal set of host factors required for filoviral glycoprotein-driven cell entry, we screened twelve cell lines and identified the nonlymphocytic cell line SH-SY5Y to be specifically resistant to filovirus infection. Heterokaryons of SH-SY5Y cells fused to susceptible cells were susceptible to filoviruses, indicating that SH-SY5Y cells do not express a restriction factor but lack an enabling factor critical for filovirus entry. However, all tested cell lines expressed functional intracellular factors. Global gene expression profiling of known cell surface entry factors and protein expression levels of analyzed attachment factors did not reveal any correlation between susceptibility and expression of a specific host factor. Using binding assays with recombinant filovirus glycoprotein, we identified cell attachment as the step impaired in filovirus entry in SH-SY5Y cells. Individual overexpression of attachment factors T-cell immunoglobulin and mucin domain 1 (TIM-1), Axl, Mer, or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) rendered SH-SY5Y cells susceptible to filovirus glycoprotein-driven transduction. Our study reveals that a lack of attachment factors limits filovirus entry and provides direct experimental support for a model of filoviral cell attachment where host factor usage at the cell surface is highly promiscuous.

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Author:Francisco Jóse Zapatero BelinchónORCiDGND, Erik Dietzel, Olga DolnikORCiD, Katinka Döhner, Rui CostaORCiDGND, Barbara Hertel, Barbora VeselkovaORCiDGND, Jared Kirui, Anneke Klintworth, Michael P. MannsORCiDGND, Stefan PöhlmannORCiDGND, Thomas Pietschmann, Thomas Krey, Sandra CiesekORCiDGND, Gisa GeroldORCiDGND, Beate SodeikORCiDGND, Stephan BeckerORCiDGND, Thomas von HahnORCiDGND
Parent Title (English):Viruses
Place of publication:Basel
Document Type:Article
Date of Publication (online):2019/03/19
Date of first Publication:2019/03/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/12/10
Tag:Filovirus cell entry; attachment factors redundancy; SH-SY5Y cell line; host–pathogen interactions
Issue:no. 3, art. 275
Page Number:26
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0