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A glycoprotein mutation that emerged during the 2013-2016 Ebola virus epidemic alters proteolysis and accelerates membrane fusion

J. Maximilian Fels, Robert H. Bortz III, Tanwee Alkutkar, Eva Mittler, View ORCID ProfileRohit K. Jangra, Jennifer S. Spence, View ORCID ProfileKartik Chandran
doi: https://doi.org/10.1101/2020.07.13.201863
J. Maximilian Fels
aDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Robert H. Bortz III
aDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Tanwee Alkutkar
aDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
bDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
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Eva Mittler
aDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Rohit K. Jangra
aDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Jennifer S. Spence
aDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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  • For correspondence: jspence008@gmail.com kartik.chandran@einsteinmed.org
Kartik Chandran
aDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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  • ORCID record for Kartik Chandran
  • For correspondence: jspence008@gmail.com kartik.chandran@einsteinmed.org
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Abstract

Genomic surveillance of viral isolates during the 2013-2016 Ebola virus epidemic in Western Africa—the largest and most devastating filovirus outbreak on record—revealed several novel mutations. The responsible strain, named Makona, carries an A to V substitution at position 82 in the glycoprotein (GP), which is associated with enhanced infectivity in vitro. Here, we investigated the mechanistic basis for this enhancement, as well as the interplay between A82V and a T to I substitution at residue 544 of GP, which also modulates infectivity in cell culture. We found that both 82V and 544I destabilize GP with the residue at 544 impacting overall stability, while 82V specifically destabilizes proteolytically cleaved GP. Both residues also promote faster kinetics of lipid mixing of the viral and host membranes in live cells, individually and in tandem, which correlates with faster times to fusion following co-localization with the viral receptor Niemann-Pick C1 (NPC1). Further, GPs bearing 82V are more sensitive to proteolysis by cathepsin L (CatL), a key host factor for viral entry. Intriguingly, CatL processed 82V variant GPs to a novel product of ∼12K size, which we hypothesize corresponds to a form of GP more fully primed for fusion than previously detected. We thus propose a model in which 82V promotes more efficient GP processing by CatL, leading to faster viral fusion kinetics and higher infectivity.

Importance The 2013-2016 outbreak of Ebola virus disease in West Africa demonstrated the potential for previously localized outbreaks to turn into regional, or even global, health emergencies. With over 28,000 cases and 11,000 confirmed deaths, this outbreak was over 50 times as large as any previously recorded. This outbreak also afforded the largest ever collection of Ebola virus genomic sequence data, allowing new insights into viral transmission and evolution. Viral mutants arising during the outbreak have attracted attention for their potentially altered patterns of infectivity in cell culture, with potential, if unclear, implications for increased viral spread and/or virulence. Here, we report on the properties of one such mutation in the viral glycoprotein, A82V, and its interplay with a previously described polymorphism at position 544. We show that mutations at both residues promote infection and fusion activation in cells, but that A82V additionally leads to increased infectivity under cathepsin-limited conditions, and the generation of a novel glycoprotein cleavage product.

Competing Interest Statement

K.C. is a member of the scientific advisory board of Integrum Scientific, LLC.

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  • Addition of new references to relevant published work.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 24, 2020.
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A glycoprotein mutation that emerged during the 2013-2016 Ebola virus epidemic alters proteolysis and accelerates membrane fusion
J. Maximilian Fels, Robert H. Bortz III, Tanwee Alkutkar, Eva Mittler, Rohit K. Jangra, Jennifer S. Spence, Kartik Chandran
bioRxiv 2020.07.13.201863; doi: https://doi.org/10.1101/2020.07.13.201863
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A glycoprotein mutation that emerged during the 2013-2016 Ebola virus epidemic alters proteolysis and accelerates membrane fusion
J. Maximilian Fels, Robert H. Bortz III, Tanwee Alkutkar, Eva Mittler, Rohit K. Jangra, Jennifer S. Spence, Kartik Chandran
bioRxiv 2020.07.13.201863; doi: https://doi.org/10.1101/2020.07.13.201863

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