A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles

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 filovi...

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Auteurs principaux:	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
Format:	article
Langue:	EN
Publié:	American Society for Microbiology 2016
Sujets:	Ebola virus NPC1 Niemann-Pick C1 endosomal receptor filovirus intracellular receptor Microbiology QR1-502
Accès en ligne:	https://doaj.org/article/3da236045f8b4c6092e8cd389a15860f
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spelling	oai:doaj.org-article:3da236045f8b4c6092e8cd389a15860f2021-11-15T15:21:21ZA Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles10.1128/mSphere.00007-162379-5042https://doaj.org/article/3da236045f8b4c6092e8cd389a15860f2016-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00007-16https://doaj.org/toc/2379-5042ABSTRACT 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. IMPORTANCE Identifying cellular factors that determine susceptibility to infection can help us understand how Ebola virus is transmitted. We asked if the EBOV receptor Niemann-Pick C1 (NPC1) could explain why reptiles are resistant to EBOV infection. We demonstrate that cells derived from the Russell’s viper are not susceptible to infection because EBOV cannot bind to viper NPC1. This resistance to infection can be mapped to a single amino acid residue in viper NPC1 that renders it unable to bind to EBOV GP. The newly solved structure of EBOV GP bound to NPC1 confirms our findings, revealing that this residue dips into the GP receptor-binding pocket and is therefore critical to the binding interface. Consequently, this otherwise well-conserved residue in vertebrate species influences the ability of reptilian NPC1 proteins to bind to EBOV GP, thereby affecting viral host range in reptilian cells.Esther NdungoAndrew S. HerbertMatthijs RaabenGregor ObernostererRohan BiswasEmily Happy MillerAriel S. WirchnianskiJan E. CaretteThijn R. BrummelkampSean P. WhelanJohn M. DyeKartik ChandranAmerican Society for MicrobiologyarticleEbola virusNPC1Niemann-Pick C1endosomal receptorfilovirusintracellular receptorMicrobiologyQR1-502ENmSphere, Vol 1, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Ebola virus NPC1 Niemann-Pick C1 endosomal receptor filovirus intracellular receptor Microbiology QR1-502
spellingShingle	Ebola virus NPC1 Niemann-Pick C1 endosomal receptor filovirus intracellular receptor Microbiology QR1-502 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 A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles
description	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. IMPORTANCE Identifying cellular factors that determine susceptibility to infection can help us understand how Ebola virus is transmitted. We asked if the EBOV receptor Niemann-Pick C1 (NPC1) could explain why reptiles are resistant to EBOV infection. We demonstrate that cells derived from the Russell’s viper are not susceptible to infection because EBOV cannot bind to viper NPC1. This resistance to infection can be mapped to a single amino acid residue in viper NPC1 that renders it unable to bind to EBOV GP. The newly solved structure of EBOV GP bound to NPC1 confirms our findings, revealing that this residue dips into the GP receptor-binding pocket and is therefore critical to the binding interface. Consequently, this otherwise well-conserved residue in vertebrate species influences the ability of reptilian NPC1 proteins to bind to EBOV GP, thereby affecting viral host range in reptilian cells.
format	article
author	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
author_facet	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
author_sort	Esther Ndungo
title	A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles
title_short	A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles
title_full	A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles
title_fullStr	A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles
title_full_unstemmed	A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles
title_sort	single residue in ebola virus receptor npc1 influences cellular host range in reptiles
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/3da236045f8b4c6092e8cd389a15860f
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A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles

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