A single residue in Ebola virus receptor NPC1 influences cellular host range in reptiles

Esther Ndungo, Andrew S. Herbert, Matthijs Raaben, Gregor Obernosterer, Rohan Biswas, Emily Happy Miller, Ariel S. Wirchnianski, Jan E. Carette, Thijn R. Brummelkamp, Sean P. Whelan, John M. Dye, Kartik Chandran

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Filoviruses are the causative agents of an increasing number of disease outbreaks in human populations, including the current unprecedented Ebola virus disease (EVD) outbreak in western Africa. One obstacle to controlling these epidemics is our poor understanding of the host range of filoviruses and their natural reservoirs. Here, we investigated the role of the intracellular filovirus receptor, Niemann-Pick C1 (NPC1) as a molecular determinant of Ebola virus (EBOV) host range at the cellular level. Whereas human cells can be infected by EBOV, a cell line derived from a Russell's viper (Daboia russellii) (VH-2) is resistant to infection in an NPC1-dependent manner. We found that VH-2 cells are resistant to EBOV infection because the Russell's viper NPC1 ortholog bound poorly to the EBOV spike glycoprotein (GP). Analysis of panels of viper-human NPC1 chimeras and point mutants allowed us to identify a single amino acid residue in NPC1, at position 503, that bidirectionally influenced both its binding to EBOV GP and its viral receptor activity in cells. Significantly, this single residue change perturbed neither NPC1's endosomal localization nor its housekeeping role in cellular cholesterol trafficking. Together with other recent work, these findings identify sequences in NPC1 that are important for viral receptor activity by virtue of their direct interaction with EBOV GP and suggest that they may influence filovirus host range in nature. Broader surveys of NPC1 orthologs from vertebrates may delineate additional sequence polymorphisms in this gene that control susceptibility to filovirus infection.

Original languageEnglish (US)
Article numbere00007-16
JournalmSphere
Volume1
Issue number2
DOIs
StatePublished - Mar 1 2016

Fingerprint

Ebolavirus
Virus Receptors
Reptiles
Host Specificity
Ebola Hemorrhagic Fever
Russell's Viper
Disease Outbreaks
Glycoproteins
Housekeeping
Western Africa
Infection
Vertebrates
Cholesterol
Amino Acids
Cell Line
Population
Genes

Keywords

  • Ebola virus
  • Endosomal receptor
  • Filovirus
  • Intracellular receptor
  • Niemann-Pick C1
  • NPC1
  • Reptiles
  • Viral receptor
  • Virus-host interactions

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

Cite this

Ndungo, E., Herbert, A. S., Raaben, M., Obernosterer, G., Biswas, R., Miller, E. H., ... Chandran, K. (2016). A single residue in Ebola virus receptor NPC1 influences cellular host range in reptiles. mSphere, 1(2), [e00007-16]. https://doi.org/10.1128/mSphere.00007-16

A single residue in Ebola virus receptor NPC1 influences cellular host range in reptiles. / Ndungo, Esther; Herbert, Andrew S.; Raaben, Matthijs; Obernosterer, Gregor; Biswas, Rohan; Miller, Emily Happy; Wirchnianski, Ariel S.; Carette, Jan E.; Brummelkamp, Thijn R.; Whelan, Sean P.; Dye, John M.; Chandran, Kartik.

In: mSphere, Vol. 1, No. 2, e00007-16, 01.03.2016.

Research output: Contribution to journalArticle

Ndungo, E, Herbert, AS, Raaben, M, Obernosterer, G, Biswas, R, Miller, EH, Wirchnianski, AS, Carette, JE, Brummelkamp, TR, Whelan, SP, Dye, JM & Chandran, K 2016, 'A single residue in Ebola virus receptor NPC1 influences cellular host range in reptiles', mSphere, vol. 1, no. 2, e00007-16. https://doi.org/10.1128/mSphere.00007-16
Ndungo E, Herbert AS, Raaben M, Obernosterer G, Biswas R, Miller EH et al. A single residue in Ebola virus receptor NPC1 influences cellular host range in reptiles. mSphere. 2016 Mar 1;1(2). e00007-16. https://doi.org/10.1128/mSphere.00007-16
Ndungo, Esther ; Herbert, Andrew S. ; Raaben, Matthijs ; Obernosterer, Gregor ; Biswas, Rohan ; Miller, Emily Happy ; Wirchnianski, Ariel S. ; Carette, Jan E. ; Brummelkamp, Thijn R. ; Whelan, Sean P. ; Dye, John M. ; Chandran, Kartik. / A single residue in Ebola virus receptor NPC1 influences cellular host range in reptiles. In: mSphere. 2016 ; Vol. 1, No. 2.
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abstract = "Filoviruses are the causative agents of an increasing number of disease outbreaks in human populations, including the current unprecedented Ebola virus disease (EVD) outbreak in western Africa. One obstacle to controlling these epidemics is our poor understanding of the host range of filoviruses and their natural reservoirs. Here, we investigated the role of the intracellular filovirus receptor, Niemann-Pick C1 (NPC1) as a molecular determinant of Ebola virus (EBOV) host range at the cellular level. Whereas human cells can be infected by EBOV, a cell line derived from a Russell's viper (Daboia russellii) (VH-2) is resistant to infection in an NPC1-dependent manner. We found that VH-2 cells are resistant to EBOV infection because the Russell's viper NPC1 ortholog bound poorly to the EBOV spike glycoprotein (GP). Analysis of panels of viper-human NPC1 chimeras and point mutants allowed us to identify a single amino acid residue in NPC1, at position 503, that bidirectionally influenced both its binding to EBOV GP and its viral receptor activity in cells. Significantly, this single residue change perturbed neither NPC1's endosomal localization nor its housekeeping role in cellular cholesterol trafficking. Together with other recent work, these findings identify sequences in NPC1 that are important for viral receptor activity by virtue of their direct interaction with EBOV GP and suggest that they may influence filovirus host range in nature. Broader surveys of NPC1 orthologs from vertebrates may delineate additional sequence polymorphisms in this gene that control susceptibility to filovirus infection.",
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