# Elucidating the Mechanism of Ebola Virus Enterotoxigenicity

> **NIH NIH FI2** · U.S. NATIONAL INST ALLERGY & INFECT DIS · 2020 · —

## Abstract

PROJECT SUMMARY
Ebola Virus Disease (EVD) is highly lethal with >20,000 cases reported during the 2014-16 West Africa epidemic
and >2,800 cases reported during the ongoing epidemic in the Democratic Republic of the Congo. Ebola virus
(EBOV) belongs to the Filoviridae family and encodes for 7 proteins including a single glycoprotein (EBOV-GP)
that has been shown to play a crucial role in EVD pathogenesis. During EVD, gastrointestinal fluid loss via large
volume watery diarrhea leads to hypovolemic shock, electrolyte imbalances, and increased mortality.
Furthermore, feces are categorized as highly infectious, thus excessive fluid loss incites environmental
contamination increasing the risk of nosocomial viral transmission. The physiological mechanisms of viral
glycoproteins acting as enterotoxins and prompting high volume diarrhea have been well described.
However, the molecular trigger and mechanisms describing how EBOV stimulates high volume watery diarrhea
during EVD have never been studied. Our preliminary data in human intestinal cells suggests an enterotoxin-
like behavior for EBOV-GP as it induces a rapid and dose-dependent increase in intracellular Ca2+
concentration that is mitigated by inhibition of Phospholipase C (PLC). Moreover, EBOV-GP stimulation
induces activation of chloride channels. The working hypothesis is that EBOV-GP induces intracellular Ca2+
increase in the gastroinstestinal epithelia, triggering an apical surface ion transport dysregulation resulting in
increased permeability and water secretion. The project goals are to determine if EBOV-GP acts as an
enterotoxin, study if it triggers a malabsorptive or secretory process and fully elucidate the mechanisms leading
to high-volume watery diarrhea during EVD. For this, the project has three specific aims conceptualized for using
of small intestine and colon cells since they diverge in absorption and secretion processes. Aim 1 will study the
contributions of Ca2+ sources in the increased levels of intracellular Ca2+ triggered by EBOV-GP and elucidate
its upstream signaling pathway. Aim 2 will assess the dynamics of Na+ and Cl- across the cell membrane, cell
permeability and fluid transport after EBOV-GP stimulation. Polarized cell cultures will be used to mimic the
ions/fluid movement and directionality. Aim 3 will feature whole-cell patch clamp to identify the ion channels
being altered by EBOV-GP. This project will be achieved using contemporary in-vitro assays and combine
microscopy, molecular biology, electrophysiology and biophysics. The completion of this project will provide the
awardee training in electrophysiology techniques advancing his career and complementing his immunology and
cell biology background. The proposed project will provide the awardee the skill set to study host-pathogen
interactions in the context of the interplay between electrophysiology, immunology and cell biology. This project
has translational impact as it could lead to novel therapeutic target...

## Key facts

- **NIH application ID:** 10025919
- **Project number:** 1FI2GM137804-01
- **Recipient organization:** U.S. NATIONAL INST ALLERGY & INFECT DIS
- **Principal Investigator:** Marcos Javier Ramos-Benitez
- **Activity code:** FI2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025919

## Citation

> US National Institutes of Health, RePORTER application 10025919, Elucidating the Mechanism of Ebola Virus Enterotoxigenicity (1FI2GM137804-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10025919. Licensed CC0.

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