Ebola virus delta peptide is an enterotoxin.

Lilia I Melnik,William C Wimley,Brandon J Beddingfield,Allison R Smither,Jenisha Ghimire,William R Gallaher,Robert F Garry,Andrew R Hoffmann,Erik K Flemington,Leisheng Sun,Shantanu Guha,Nathan A Ungerleider,Melody C Baddoo

doi:10.1016/j.celrep.2021.110172

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 EBOV-induced gastrointestinal pathology.

Highlights

Ebola virus (EBOV, species Zaire ebolavirus, family Filoviridae) is the causative agent of EBOV disease (EVD), a frequently emerging infectious disease with a high fatality rate
E23ox induces fluid secretion in a murine ligated ileal loop model of diarrheal disease To determine whether EBOV delta peptide can function as an enterotoxin, we tested E23ox in an established animal model of diarrheal disease (Sawasvirojwong et al, 2013) (Figure 2)
One hundred microliters of either 0.025% acetic acid, 107 CFU/ loop of V. cholerae, or 10, 20, 50, or 100 mM E23ox was injected into ileal loops, which were examined at 6, 9, 12, and 24 h after surgery (n = 8–36 mice/group) (Figure 2B)

Summary

Introduction

Ebola virus (EBOV, species Zaire ebolavirus, family Filoviridae) is the causative agent of EBOV disease (EVD), a frequently emerging infectious disease with a high fatality rate. A recent EVD outbreak that began in August 2018 in eastern Democratic Republic of the Congo (DRC) and resulted in 3,462 confirmed cases and 2,267 deaths was declared over in June 2020 (Kraemer et al, 2020). The 2013–2016 West African (WA) EVD outbreak remains the largest and most geographically dispersed to date, with 28,652 confirmed and suspected cases and 11,325 recorded deaths, principally in Guinea, Sierra Leone, and Liberia (Boisen et al, 2016; Goba et al, 2016; Hartnett et al, 2015). Phylogenetic analyses suggest that the ancestor of EBOV Makona diverged from Central African EBOV around 2004 (Gire et al, 2014). This analysis suggested that the WA EVD outbreak was initiated by a single spillover event into the human population and that efficient human-to-human transmission sustained the outbreak

Results

Discussion

Conclusion