Filoviruses Require Endosomal Cysteine Proteases for Entry but Exhibit Distinct Protease Preferences

John Misasi, Kartik Chandran, Jin Yi Yang, Bryden Considine, Claire Marie Filone, Marceline Côté, Nancy Sullivan, Giulia Fabozzi, Lisa Hensley, James Cunninghama

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Filoviruses are enveloped viruses that cause sporadic outbreaks of severe hemorrhagic fever [CDC,MMWRMorb. Mortal. Wkly. Rep. 50:73-77, 2001; Colebunders and Borchert, J. Infect. 40:16-20, 2000; Colebunders et al., J. Infect. Dis. 196(Suppl. 2):S148-S153, 2007; Geisbert and Jahrling, Nat. Med. 10:S110-S121, 2004]. Previous studies revealed that endosomal cysteine proteases are host factors for ebolavirus Zaire (Chandran et al., Science 308:1643-1645, 2005; Schornberg et al., J. Virol. 80:4174-4178, 2006). In this report, we show that infection mediated by glycoproteins from other phylogenetically diverse filoviruses are also dependent on these proteases and provide additional evidence indicating that they cleave GP1 and expose the binding domain for the critical host factor Niemann-Pick C1. Using selective inhibitors and knockout-derived cell lines, we show that the ebolaviruses Zaire and Cote d'Ivoire are strongly dependent on cathepsin B, while the ebolaviruses Sudan and Reston and Marburg virus are not. Taking advantage of previous studies of cathepsin B inhibitor-resistant viruses (Wong et al., J. Virol. 84:163-175, 2010), we found that virus-specific differences in the requirement for cathepsin B are correlated with sequence polymorphisms at residues 47 in GP1 and 584 in GP2. We applied these findings to the analysis of additional ebolavirus isolates and correctly predicted that the newly identified ebolavirus species Bundibugyo, containing D47 and I584, is cathepsin B dependent and that ebolavirus Zaire-1995, the single known isolate of ebolavirus Zaire that lacks D47, is not. We also obtained evidence for virusspecific differences in the role of cathepsin L, including cooperation with cathepsin B. These studies strongly suggest that the use of endosomal cysteine proteases as host factors for entry is a general property of members of the family Filoviridae.

Original languageEnglish (US)
Pages (from-to)3284-3292
Number of pages9
JournalJournal of virology
Volume86
Issue number6
DOIs
StatePublished - Mar 1 2012

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Misasi, J., Chandran, K., Yang, J. Y., Considine, B., Filone, C. M., Côté, M., Sullivan, N., Fabozzi, G., Hensley, L., & Cunninghama, J. (2012). Filoviruses Require Endosomal Cysteine Proteases for Entry but Exhibit Distinct Protease Preferences. Journal of virology, 86(6), 3284-3292. https://doi.org/10.1128/JVI.06346-11