# Research Project 1: Role of Epigenetic and Transcriptional Mechanisms in the Pathogenesis of Ebola Virus Disease

> **NIH NIH P01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $425,513

## Abstract

RESEARCH PROJECT 1 (RP1): PROJECT SUMMARY/ABSTRACT
Pathogenesis of the disease caused by Ebola virus (EBOV) is characterized by a multifaceted and contradictory
interplay between the virus and the host. The effect of EBOV infection is characterized by deficient T-cell
responses and lymphopenia, which at least in part results from stimulation by virus-infected dendritic cells whose
maturation is suppressed by interferon-inhibiting domains of the virus. In addition, EBOV infections are
characterized by hyperinflammation, contributed by interaction of the EBOV envelope glycoprotein (GP) with
TLR4 on T cells and possibly by other mechanisms, resulting in massive secretion of cytokines. This
dysregulated immune response results from disruption of transcriptional networks, many caused by alterations
in the epigenome, as evidenced by (1) chemical inhibition of type 1 topoisomerase resulting in reduced
expression of proinflammatory mediators induced by EBOV in infected cells, (2) inhibition of TLR4 signaling,
which is regulated at epigenetic level, promoting survival of EBOV-infected mice, and (3) treatment of EBOV-
infected mice with a global histone methylation inhibitor that upregulates production of IFNα and protects animals
from death.
The central hypothesis of Research Project 1 (RP1) is that cell-specific and gene-specific regulation of
transcription in response to EBOV infection leads to contrasting responses that paradoxically cause a pathogenic
immune response and “immune paralysis”. To address this hypothesis, the epigenetic and transcriptional
landscape during EBOV infections in vitro and in vivo will be characterized. A comprehensive analysis of the
transcriptome alterations and epigenetic changes caused by EBOV infection will be performed in both human
primary cells and specific cell types isolated from infected nonhuman primates. Investigations involving the
expression of mRNAs that encode transcription factors will be done to determine the deposition of epigenetic
marks and their role in gene activation and repression, as well as investigating the effects of chromatin
accessibility on expression and secretion of inflammatory mediators using cells from human donors.
This project will target key transcriptional nodes identified by modeling EBOV infection. The data generated in
vitro and in vivo, together with data from in RP2 and RP3, will be integrated by the Bioinformatics and
Modelling Core (Core D) in a model. The transcriptional networks identified in the model will predict critical
nodes that represent vulnerabilities that will be targeted to modulate cell response and reduce EBOV
pathogenesis. For example, chromatin-resident enzymes and transcription factors that induce expression of
genes causing inflammation and other pathological changes will be targeted.
The study will result in the characterization of epigenetic and transcriptional responses to EBOV; to date no
epigenetic response to any BSL-4 level virus has been characterized....

## Key facts

- **NIH application ID:** 10188759
- **Project number:** 1P01AI150585-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Alexander Bukreyev
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $425,513
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188759

## Citation

> US National Institutes of Health, RePORTER application 10188759, Research Project 1: Role of Epigenetic and Transcriptional Mechanisms in the Pathogenesis of Ebola Virus Disease (1P01AI150585-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10188759. Licensed CC0.

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