Ebola Virus Delta-Peptide Acts as an Enterotoxic Viroporin In Vivo

Abstract

Ebola virus (EBOV), part of the filovirus family, has a genome that encodes for a partly conserved, 40-residue polypeptide, called the delta peptide, which is produced during Ebola virus disease pathogenesis. Sequence-structure analysis and a wealth of in vitro data suggest that the delta peptide is a viroporin, a diverse family of pore-forming peptides and proteins involved in replication and pathogenesis of numerous viruses. Specifically, many filovirus delta peptides have a high abundance of cationic and aromatic residues while maintaining amphipathicity; these are properties that are common in membrane-permeabilizing peptides. Full-length and conserved C-terminal EBOV delta peptide fragments were shown to permeabilize synthetic lipid bilayers and multiple cell types in vitro. Here, we follow up those results with an established mouse model of diarrheal pathology focusing on the small intestine. We hypothesized that the lytic activity observed against numerous cell types in vitro would also be apparent when testing the delta peptide in vivo. We found that the delta peptide exerts potent, dose-dependent enterotoxic activity against intestinal cells upon introduction to a closed intestinal loop. The peak activity of the peptide, which results in a diarrheal syndrome in the mice, occurs 9-12 hours after introduction to the small intestine. This conclusion is confirmed with histology studies in which we examined intestinal architecture and found that it was severely damaged by the delta peptide. Further, the density of mucin-producing goblet cells in villi was diminished by the peptide. These results show that the EBOV delta peptide is a potential novel therapeutic target, and neutralizing it could ameliorate some of the severe enterotoxic burden characteristic of EBOV disease pathogenesis.