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Author Notes:

liushan@missouri.edu (SLL); Fredric_Cohen@rush.edu (FSC)

Conceived and designed the experiments: FSC RMM SLL GBM. Performed the experiments: RMM CM YMZ. Analyzed the data: RMM CM YMZ GBM SLL FSC. Contributed reagents/materials/analysis tools: RMM CM YMZ GBM SSL. Wrote the paper: RMM GBM SLL FSC.

We thank Kartik Chandran, James Cunningham, David Sanders, and Gary Kobinger for provision of reagents that made this work possible.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.


Research Funding:

This work was supported by grants from NIH for FSC (R01 GM101539), SLL (R01 AI112381, R21 AI109464, R21 AI105584 and U54 AI057160) and GBM (R01 AI053668).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Microbiology
  • Parasitology
  • Virology

Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger


Journal Title:

PLoS Pathogens


Volume 12, Number 1


, Pages e1005373-e1005373

Type of Work:

Article | Final Publisher PDF


Ebola virus (EBOV) is a highly pathogenic filovirus that causes hemorrhagic fever in humans and animals. Currently, how EBOV fuses its envelope membrane within an endosomal membrane to cause infection is poorly understood. We successfully measure cell-cell fusion mediated by the EBOV fusion protein, GP, assayed by the transfer of both cytoplasmic and membrane dyes. A small molecule fusion inhibitor, a neutralizing antibody, as well as mutations in EBOV GP known to reduce viral infection, all greatly reduce fusion. By monitoring redistribution of small aqueous dyes between cells and by electrical capacitance measurements, we discovered that EBOV GP-mediated fusion pores do not readily enlarge—a marked difference from the behavior of other viral fusion proteins. EBOV GP must be cleaved by late endosome-resident cathepsins B or L in order to become fusion-competent. Cleavage of cell surface-expressed GP appears to occur in endosomes, as evidenced by the fusion block imposed by cathepsin inhibitors, agents that raise endosomal pH, or an inhibitor of anterograde trafficking. Treating effector cells with a recombinant soluble cathepsin B or thermolysin, which cleaves GP into an active form, increases the extent of fusion, suggesting that a fraction of surface-expressed GP is not cleaved. Whereas the rate of fusion is increased by a brief exposure to acidic pH, fusion does occur at neutral pH. Importantly, the extent of fusion is independent of external pH in experiments in which cathepsin activity is blocked and EBOV GP is cleaved by thermolysin. These results imply that low pH promotes fusion through the well-known pH-dependent activity of cathepsins; fusion induced by cleaved EBOV GP is a process that is fundamentally independent of pH. The cell-cell fusion system has revealed some previously unappreciated features of EBOV entry, which could not be readily elucidated in the context of endosomal entry.

Copyright information:

© 2016 Markosyan et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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