# Dissecting the mechanisms of intestinal epithelial injury by Ebola virus using iPSC-derived intestinal organoids

> **NIH NIH R21** · BOSTON MEDICAL CENTER · 2022 · $273,750

## Abstract

Project Summary
Filoviruses, including ebola- and marburgviruses, are prime examples of zoonotic viruses that cause severe
disease in humans. The most pathogenic ebolavirus species is Ebola virus (Zaire ebolavirus; EBOV) with case
fatality rates ranging from 40 to 90%. Many patients who succumb to the disease are admitted to Ebola treatment
units when they are already severely ill. Importantly, there are no therapeutics available to mitigate late-stage
Ebola Virus Disease (EVD). While many aspects of EBOV pathogenesis have been extensively studied in cell
culture systems and animal models, the involvement of the intestine in EVD is not at all understood, despite
diarrhea being among the most frequent symptoms (78% of patients in some case studies) and being one of the
main causes for demise. Gastrointestinal manifestations, including vomiting, abdominal pain, and diarrhea, are
also common symptoms of Marburg virus (MARV) disease. There are currently no infection models available
that allow to study the consequences of filovirus infection of the gut. To fill this gap, we propose to establish
human intestinal infection platforms to dissect the molecular mechanisms underlying filovirus-induced damage
of the intestinal organs. We will explore two potential mechanisms that might play a role in the pathophysiological
effects induced by filovirus infection: i) Filovirus infection of the human intestinal epithelium leads to loss of barrier
integrity. ii) Filovirus infection of the human intestinal epithelium modulates the function of ion transporters.
Identifying mechanisms that contribute to the induction of severe diarrhea in filovirus infection has the potential
to inform urgently needed therapeutic approaches to mitigate the severe intestinal symptoms in late-stage
filovirus disease.
Human induced pluripotent stem cells (iPSCs) are capable of indefinite self-renewal and have the potential to
differentiate into any tissue-specific cell lineage, including human intestinal organoids (HIOs). In preparation for
this project, we have successfully achieved robust EBOV and MARV infections of iPSC-derived HIOs. The
infected cells showed signs of cell damage, and transcriptomics analysis indicated the modulation of cell junction
pathways and a set of ion transporters known to play a role in the induction of diarrhea. To begin to explore the
intrinsic host response of intestinal cells to filovirus infection and the impact of infection-induced cellular damage
on barrier integrity, we have designed the following specific aims:
Specific Aim 1: To study the pathophysiological effects of EBOV and MARV infection on intestinal
epithelial integrity.
Specific Aim 2: To validate the role of individual genes by genetic ablation and test potential drug
candidates as modulators of intestinal epithelial function.

## Key facts

- **NIH application ID:** 10538716
- **Project number:** 1R21AI167369-01A1
- **Recipient organization:** BOSTON MEDICAL CENTER
- **Principal Investigator:** Gustavo Mostoslavsky
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $273,750
- **Award type:** 1
- **Project period:** 2022-07-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538716

## Citation

> US National Institutes of Health, RePORTER application 10538716, Dissecting the mechanisms of intestinal epithelial injury by Ebola virus using iPSC-derived intestinal organoids (1R21AI167369-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10538716. Licensed CC0.

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