Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry Into Cells

Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)–mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protrudin...

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Published in	The Journal of infectious diseases Vol. 218; no. suppl_5; pp. S397 - S402
Main Authors	Kondoh, Tatsunari, Letko, Michael, Munster, Vincent J, Manzoor, Rashid, Maruyama, Junki, Furuyama, Wakako, Miyamoto, Hiroko, Shigeno, Asako, Fujikura, Daisuke, Takadate, Yoshihiro, Yoshida, Reiko, Igarashi, Manabu, Feldmann, Heinz, Marzi, Andrea, Takada, Ayato
Format	Journal Article
Language	English
Published	United States Oxford University Press 22.11.2018
Subjects	Animals Carrier Proteins - genetics Cell Line Chlorocebus aethiops Ebolavirus - pathogenicity HEK293 Cells Hemorrhagic Fever, Ebola - genetics Hemorrhagic Fever, Ebola - virology Humans Membrane Glycoproteins - genetics Polymorphism, Single Nucleotide - genetics Receptors, Virus - metabolism Supplement Vero Cells Viral Envelope Proteins - metabolism Virus Internalization
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Abstract	Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)–mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protruding loops in domain C of NPC1. Using previously published structural data and the National Center for Biotechnology Information Single-Nucleotide Polymorphism (SNP) database, we identified 10 naturally occurring missense SNPs in human NPC1. To investigate whether these SNPs affect cell susceptibility to filovirus infection, we generated Vero E6 cell lines stably expressing NPC1 with SNP substitutions and compared their susceptibility to vesicular stomatitis virus pseudotyped with filovirus GPs and infectious EBOV. We found that some of the substitutions resulted in reduced susceptibility to filoviruses, as indicated by the lower titers and smaller plaque/focus sizes of the viruses. Our data suggest that human NPC1 SNPs may likely affect host susceptibility to filoviruses.
AbstractList	Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)–mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protruding loops in domain C of NPC1. Using previously published structural data and the National Center for Biotechnology Information Single-Nucleotide Polymorphism (SNP) database, we identified 10 naturally occurring missense SNPs in human NPC1. To investigate whether these SNPs affect cell susceptibility to filovirus infection, we generated Vero E6 cell lines stably expressing NPC1 with SNP substitutions and compared their susceptibility to vesicular stomatitis virus pseudotyped with filovirus GPs and infectious EBOV. We found that some of the substitutions resulted in reduced susceptibility to filoviruses, as indicated by the lower titers and smaller plaque/focus sizes of the viruses. Our data suggest that human NPC1 SNPs may likely affect host susceptibility to filoviruses. Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)-mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protruding loops in domain C of NPC1. Using previously published structural data and the National Center for Biotechnology Information Single-Nucleotide Polymorphism (SNP) database, we identified 10 naturally occurring missense SNPs in human NPC1. To investigate whether these SNPs affect cell susceptibility to filovirus infection, we generated Vero E6 cell lines stably expressing NPC1 with SNP substitutions and compared their susceptibility to vesicular stomatitis virus pseudotyped with filovirus GPs and infectious EBOV. We found that some of the substitutions resulted in reduced susceptibility to filoviruses, as indicated by the lower titers and smaller plaque/focus sizes of the viruses. Our data suggest that human NPC1 SNPs may likely affect host susceptibility to filoviruses.Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)-mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protruding loops in domain C of NPC1. Using previously published structural data and the National Center for Biotechnology Information Single-Nucleotide Polymorphism (SNP) database, we identified 10 naturally occurring missense SNPs in human NPC1. To investigate whether these SNPs affect cell susceptibility to filovirus infection, we generated Vero E6 cell lines stably expressing NPC1 with SNP substitutions and compared their susceptibility to vesicular stomatitis virus pseudotyped with filovirus GPs and infectious EBOV. We found that some of the substitutions resulted in reduced susceptibility to filoviruses, as indicated by the lower titers and smaller plaque/focus sizes of the viruses. Our data suggest that human NPC1 SNPs may likely affect host susceptibility to filoviruses.
Author	Feldmann, Heinz Letko, Michael Munster, Vincent J Yoshida, Reiko Manzoor, Rashid Kondoh, Tatsunari Fujikura, Daisuke Takada, Ayato Maruyama, Junki Igarashi, Manabu Shigeno, Asako Takadate, Yoshihiro Miyamoto, Hiroko Furuyama, Wakako Marzi, Andrea
AuthorAffiliation	1 Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan 4 Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana 3 Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan 5 School of Veterinary Medicine, the University of Zambia, Lusaka 2 Division of Infection and Immunity, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan
AuthorAffiliation_xml	– name: 5 School of Veterinary Medicine, the University of Zambia, Lusaka – name: 1 Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan – name: 2 Division of Infection and Immunity, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan – name: 4 Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana – name: 3 Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present affiliations: Department of Pathology, University of Texas Medical Branch, Galveston (J. M.); Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana (W. F.); and Center for Advanced Research and Education, Asahikawa Medical University, Japan (D. F.).
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Snippet	Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)–mediated entry of filoviruses into cells, is believed to be a major... Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)-mediated entry of filoviruses into cells, is believed to be a major...
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SubjectTerms	Animals Carrier Proteins - genetics Cell Line Chlorocebus aethiops Ebolavirus - pathogenicity HEK293 Cells Hemorrhagic Fever, Ebola - genetics Hemorrhagic Fever, Ebola - virology Humans Membrane Glycoproteins - genetics Polymorphism, Single Nucleotide - genetics Receptors, Virus - metabolism Supplement Vero Cells Viral Envelope Proteins - metabolism Virus Internalization
Title	Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry Into Cells
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