# Ebola virus matrix protein VP40 triggers inflammatory responses linked to the ebolavirus virulence

## TL;DR

This study shows that the Ebola virus protein VP40 causes strong inflammation in nonimmune cells, contributing to the virus's severity.

## Contribution

The study identifies VP40 as a virulence factor that drives inflammation through NF-κB activation in nonimmune cells.

## Key findings

- VP40 from highly virulent EBOV causes stronger inflammation than less virulent strains.
- VP40 activates NF-κB via TNFR1 without needing a ligand.
- Nonimmune cells are a major source of inflammation in EBOV infections.

## Abstract

This study investigates how the Ebola virus (EBOV) triggers excessive inflammation, which is a critical factor in the fatal Ebola virus disease (EVD). We found that the EBOV matrix protein, VP40, leads to strong and prolonged activation of NF-κB in nonimmune cells. This suggests a mechanism for the widespread inflammation observed in EVD patients. Notably, VP40 from highly virulent EBOV induced a stronger inflammatory response compared to those from less virulent ebolaviruses. Therefore, this study proposes that VP40 functions as a virulence determinant among ebolaviruses by mediating inflammatory activation, addressing the intriguing and unresolved question of pathogenicity differences among various ebolaviruses.

Uncontrolled systemic inflammatory responses are a critical pathological feature of fatal Ebola virus (EBOV) infection. While some inflammatory responses may originate from mononuclear phagocytes (MNPs), nonimmune cells vastly outnumber MNPs and may be an important source of inflammation. Here, we demonstrated that highly virulent EBOV induced a high and sustained pro-inflammatory response compared to less virulent ebolaviruses in non-MNPs through TLR4-independent NF-κB activation. We identified the EBOV matrix protein VP40 as a potent activator of NF-κB in non-MNPs, whose intrinsic inflammatory activation ability is higher than VP40 proteins from less virulent ebolaviruses. This suggests that VP40 is a virulence determinant inducing distinct degrees of pro-inflammatory responses among ebolaviruses. Mechanistically, VP40 activated the NF-κB signaling pathway, primarily via TNFR1 using a ligand-independent mechanism. These findings reveal mechanisms that may drive systemic inflammation and promote EBOV pathogenesis, suggesting potential therapeutic strategies to mitigate immune dysregulation in severe EBOV infections.