Ebola Virus Glycoprotein with Increased Infectivity Dominated the 2013-2016 Epidemic.
The magnitude of the 2013-2016 Ebola virus disease (EVD) epidemic enabled an unprecedented number of viral mutations to occur over successive human-to-human transmission events, increasing the probability that adaptation to the human host occurred during the outbreak. We investigated one nonsynonymous mutation, Ebola virus (EBOV) glycoprotein (GP) mutant A82V, for its effect on viral infectivity. This mutation, located at the NPC1-binding site on EBOV GP, occurred early in the 2013-2016 outbreak and rose to high frequency. We found that GP-A82V had heightened ability to infect primate cells, including human dendritic cells. The increased infectivity was restricted to cells that have primate-specific NPC1 sequences at the EBOV interface, suggesting that this mutation was indeed an adaptation to the human host. GP-A82V was associated with increased mortality, consistent with the hypothesis that the heightened intrinsic infectivity of GP-A82V contributed to disease severity during the EVD epidemic.
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
William E
WE
Diehl
Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
Aaron E
AE
Lin
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Nathan D
ND
Grubaugh
Institute of Evolutionary Biology, University of Edinburgh, Ashworth Laboratories, Kings Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland, UK.
Luiz Max
LM
Carvalho
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Kyusik
K
Kim
Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA.
Pyae Phyo
PP
Kyawe
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Sean M
SM
McCauley
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Elisa
E
Donnard
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Alper
A
Kucukural
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Patrick
P
McDonel
Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
Stephen F
SF
Schaffner
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Manuel
M
Garber
Institute of Evolutionary Biology, University of Edinburgh, Ashworth Laboratories, Kings Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland, UK.
Andrew
A
Rambaut
Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Scripps Translational Science Institute, 3344 North Torrey Pines Court, La Jolla, CA 92037, USA. Electronic address: andersen@scripps.edu.
Kristian G
KG
Andersen
Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA. Electronic address: pardis@broadinstitute.org.
Pardis C
PC
Sabeti
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA. Electronic address: jeremy.luban@umassmed.edu.
Jeremy
J
Luban
D000354:Africa, Western / Q000453:epidemiology; D019943:Amino Acid Substitution; D000818:Animals; D002144:Callithrix; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D016565:Cheirogaleidae; D003593:Cytoplasm / Q000821:virology; D029043:Ebolavirus / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D019142:Hemorrhagic Fever, Ebola / Q000453:epidemiology / Q000821:virology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D000072756:Protein Conformation, alpha-Helical; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014771:Virion / Q000737:chemistry / Q000472:pathogenicity; D014774:Virulence
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D014759:Viral Envelope Proteins; C113189:envelope glycoprotein, Ebola virus
Ebola virus; Filovirus; NPC1; RNA virus; adaptation; epidemic; glycoprotein; infection; mutation; outbreak