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 inThe 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
LanguageEnglish
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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Summary: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.
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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.).
ISSN:0022-1899
1537-6613
1537-6613
DOI:10.1093/infdis/jiy248