# Mechanisms of Ebola virus-mediated inflammatory activation linked to pathogenesis

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $663,887

## Abstract

The largest and worst Ebola virus (EBOV) disease (EVD) outbreak ever recorded occurred in West Africa from
2013-2016, and resulted in a devastatingly high death toll, economic damages, and global anxiety. EVD is one
of the most severe viral diseases, and is characterized by systemic viral replication, immune dysregulation,
coagulopathy, and multi-organ dysfunction. The synergistic effects of systemic viral replication and immune
dysregulation that characterize EVD lead to the induction of a systemic inflammatory response syndrome
(SIRS) that evokes severe systemic pathology. This complicated disease process most likely makes it difficult
to effectively treat severe/fatal EVD with therapeutics that target only the EBOV life cycle. Therefore,
understanding the mechanisms of EBOV-induced SIRS is crucial for the development of effective therapeutic
interventions that can counteract the aberrant immune activation. We have found that EBOV VP40, the viral
matrix protein that is essential for virus assembly and budding, activates host inflammatory responses and
release of pro-inflammatory cytokines in the human cells. Remarkably, we have also found that VP40 from
Reston virus and Bundibugyo virus, which belong to the same genus as EBOV but are thought to be
apathogenic or less pathogenic than EBOV in humans, activated the inflammatory pathway less efficiently than
EBOV VP40, suggesting that VP40 is a novel virulence determinant at least partially responsible for the
differential pathogenesis of these highly related viruses. Taken together, we hypothesize that the EBOV matrix
protein VP40 activates an inflammatory response through a novel mechanism, which correlates with EBOV
pathogenesis in humans. To understand this newly emerging aspect of EBOV pathogenesis, the applicant's
group and collaborators will pursue three interactive specific aims, as follows: (Aim 1) Define the significance of
unfolded protein response/ER-nucleus signaling pathway in VP40-mediated inflammatory activation; (Aim 2)
Determine the interaction of VP40 with host transcriptional machinery associated with VP40-mediated
inflammatory activation; and (Aim 3) Determine the role of EBOV VP40 as a virulence factor in inflammatory
gene activation and pathogenesis. The proposed research will provide an essential base for the development
of post-exposure therapeutic interventions that target the molecular triggers of the uncontrolled inflammatory
responses that characterize the late stages of severe EVD.

## Key facts

- **NIH application ID:** 9996478
- **Project number:** 5R01AI134937-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Michael A Barry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $663,887
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996478

## Citation

> US National Institutes of Health, RePORTER application 9996478, Mechanisms of Ebola virus-mediated inflammatory activation linked to pathogenesis (5R01AI134937-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996478. Licensed CC0.

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