Ebola virus delta peptide is an enterotoxin

Abstract

During the 2013-2016 West African (WA) Ebola virus (EBOV) outbreak, severe gastrointestinal symptoms were common in patients and associated with poor outcome. Delta peptide is a conserved product of post-translational processing of the abundant EBOV soluble glycoprotein (sGP). The murine ligated ileal loop model was used to demonstrate that delta peptide is a potent enterotoxin. Dramatic intestinal fluid accumulation follows injection of biologically relevant amounts of delta peptide into ileal loops, along with gross alteration of villous architecture and loss of goblet cells. Transcriptomic analyses show that delta peptide triggers damage response and cell survival pathways and downregulates expression of transporters and exchangers. Induction of diarrhea by delta peptide occurs via cellular damage and regulation of genes that encode proteins involved in fluid secretion. While distinct differences exist between the ileal loop murine model and EBOV infection in humans, these results suggest that delta peptide may contribute to EBOVinduced gastrointestinal pathology.

Enterotoxigenic Escherichia coli Heat-Stable Toxin and Ebola Virus Delta Peptide: Similarities and Differences

“…However, E23 alk , the C-terminal portion of EBOV delta peptide that does not contain the disulfide bond due to sulfhydryl alkylation, induced a moderate diarrheal response compared to E23 ox . These results suggest that the secondary structure of Ebola virus delta peptide is important for induction of fluid secretion [90].…”

“…Ebola virus causes various pathologies in humans and animals that include gastrointestinal disease. The role of the enterotoxigenic EBOV delta peptide [90] has yet to be completely explored and may inform future investigations.…”

“…As the diarrheal response due to delta peptide treatment was subsiding at 24 h after treatment, these architectural changes were reversed as the tissue was returning to its original shape. More importantly, 24 h after treatment with E23 ox , intestinal mucosa was undergoing a repair process characterized by the appearance of villi with blunt tips reminiscent of newly grown villi, decrease in crypt length, and the appearance of mucin-containing goblet cells [90].…”

“…Na + /K + ATPase is also responsible for the transport of Na + ions from epithelial cells to the bloodstream [137,138]. RNA-seq analyses performed by Melnik and coworkers showed that E23 ox reduced the expression of Slc5a, which codes for SGLT-1, suggesting that the coupled transport of sodium and glucose might be impaired during Ebola infection [90]. It has been reported previously that NSP4 of rotavirus inhibits SGLT-1 in mouse colon [139] and in rabbit intestinal brush border membrane [140].…”

“…Sodium/hydrogen exchanger NHE3 works in concert with chloride/bicarbonate exchanger DRA to allow absorption of electroneutral sodium chloride [144]. The expression of Slc9a3r1, which codes for NHE3, and Slc26a3 and Slc26a6, which code for DRA exchangers, was downregulated as the result of treatment with E23 ox , which might result in reduced absorption of electroneutral NaCl [90]. Slc26a3 transcript encodes an exchanger that has the stoichiometry of two chloride ions and one bicarbonate ion, while Slc26a6 encodes an exchanger has been shown to allow the exchange of one chloride ion and two bicarbonates ions [145,146].…”