Ebola virus entry requires the cholesterol transporter Niemann-Pick C1

Jan E. Carette, Matthijs Raaben, Anthony C. Wong, Andrew S. Herbert, Gregor Obernosterer, Nirupama Mulherkar, Ana I. Kuehne, Philip J. Kranzusch, April M. Griffin, Gordon Ruthel, Paola Dal Cin, John M. Dye, Sean P. Whelan, Kartik Chandran, Thijn R. Brummelkamp

Research output: Contribution to journalArticle

611 Citations (Scopus)

Abstract

Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.

Original languageEnglish (US)
Pages (from-to)340-343
Number of pages4
JournalNature
Volume477
Issue number7364
DOIs
StatePublished - Sep 15 2011

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Ebolavirus
Virus Internalization
Ebola Hemorrhagic Fever
Endosomes
Cholesterol
Antiviral Agents
Glycoproteins
Marburgvirus
Type C Niemann-Pick Disease
Mutation
Membrane Fusion
Haploidy
Protein Transport
Vacuoles
Lysosomes
Virion
Proteins
Fever
Fibroblasts
Genome

ASJC Scopus subject areas

  • General

Cite this

Carette, J. E., Raaben, M., Wong, A. C., Herbert, A. S., Obernosterer, G., Mulherkar, N., ... Brummelkamp, T. R. (2011). Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature, 477(7364), 340-343. https://doi.org/10.1038/nature10348

Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. / Carette, Jan E.; Raaben, Matthijs; Wong, Anthony C.; Herbert, Andrew S.; Obernosterer, Gregor; Mulherkar, Nirupama; Kuehne, Ana I.; Kranzusch, Philip J.; Griffin, April M.; Ruthel, Gordon; Cin, Paola Dal; Dye, John M.; Whelan, Sean P.; Chandran, Kartik; Brummelkamp, Thijn R.

In: Nature, Vol. 477, No. 7364, 15.09.2011, p. 340-343.

Research output: Contribution to journalArticle

Carette, JE, Raaben, M, Wong, AC, Herbert, AS, Obernosterer, G, Mulherkar, N, Kuehne, AI, Kranzusch, PJ, Griffin, AM, Ruthel, G, Cin, PD, Dye, JM, Whelan, SP, Chandran, K & Brummelkamp, TR 2011, 'Ebola virus entry requires the cholesterol transporter Niemann-Pick C1', Nature, vol. 477, no. 7364, pp. 340-343. https://doi.org/10.1038/nature10348
Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011 Sep 15;477(7364):340-343. https://doi.org/10.1038/nature10348
Carette, Jan E. ; Raaben, Matthijs ; Wong, Anthony C. ; Herbert, Andrew S. ; Obernosterer, Gregor ; Mulherkar, Nirupama ; Kuehne, Ana I. ; Kranzusch, Philip J. ; Griffin, April M. ; Ruthel, Gordon ; Cin, Paola Dal ; Dye, John M. ; Whelan, Sean P. ; Chandran, Kartik ; Brummelkamp, Thijn R. / Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. In: Nature. 2011 ; Vol. 477, No. 7364. pp. 340-343.
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