Ebola Virus Glycoprotein with Increased Infectivity Dominated the 2013-2016 Epidemic

William E Diehl; Aaron E Lin; Nathan D Grubaugh; Luiz Max Carvalho; Kyusik Kim; Pyae Phyo Kyawe; Sean M McCauley; Elisa Donnard; Alper Kucukural; Patrick McDonel; Stephen F Schaffner; Manuel Garber; Andrew Rambaut; Kristian G Andersen; Pardis C Sabeti; Jeremy Luban

doi:10.1016/j.cell.2016.10.014

Ebola Virus Glycoprotein with Increased Infectivity Dominated the 2013-2016 Epidemic

Cell. 2016 Nov 3;167(4):1088-1098.e6. doi: 10.1016/j.cell.2016.10.014.

Authors

William E Diehl¹, Aaron E Lin², Nathan D Grubaugh³, Luiz Max Carvalho⁴, Kyusik Kim¹, Pyae Phyo Kyawe⁵, Sean M McCauley¹, Elisa Donnard⁶, Alper Kucukural⁶, Patrick McDonel⁶, Stephen F Schaffner², Manuel Garber⁶, Andrew Rambaut⁴, Kristian G Andersen⁷, Pardis C Sabeti⁸, Jeremy Luban⁹

Affiliations

¹ Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
² Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
³ Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁴ Institute of Evolutionary Biology, University of Edinburgh, Ashworth Laboratories, Kings Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland, UK.
⁵ Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01605, USA.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA. Electronic address: jeremy.luban@umassmed.edu.

Abstract

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.

Keywords: Ebola virus; Filovirus; NPC1; RNA virus; adaptation; epidemic; glycoprotein; infection; mutation; outbreak.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Africa, Western / epidemiology
Amino Acid Substitution
Animals
Callithrix
Carrier Proteins / chemistry
Carrier Proteins / metabolism
Cheirogaleidae
Cytoplasm / virology
Ebolavirus / genetics*
Ebolavirus / pathogenicity*
Ebolavirus / physiology
Hemorrhagic Fever, Ebola / epidemiology
Hemorrhagic Fever, Ebola / virology*
Humans
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins / chemistry
Membrane Glycoproteins / metabolism
Niemann-Pick C1 Protein
Protein Conformation, alpha-Helical
Viral Envelope Proteins / chemistry*
Viral Envelope Proteins / genetics*
Viral Envelope Proteins / metabolism
Virion / chemistry
Virion / pathogenicity
Virulence

Substances

Carrier Proteins
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins
NPC1 protein, human
Niemann-Pick C1 Protein
Viral Envelope Proteins
envelope glycoprotein, Ebola virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding