Novel Mechanism of Inflammatory Activation by Ebola Virus Matrix Protein Linked to the Ebolavirus Virulence
Yamaoka, S.; MHamdi, Z.; Wang, L.; Swenson, V. A.; McNally, K. L.; Lu, S.-C.; Singh, R.; Saundh, S. L.; Zell, B. N.; Best, S. M.; Barry, M. A.; Rasmussen, A. L.; Ebihara, H.
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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), non-immune 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-{kappa}B activation. We identified the EBOV matrix protein VP40 as a potent activator of NF-{kappa}B in non-MNPs, whose intrinsic inflammatory activation ability is higher than VP40 proteins from less virulent ebolaviruses. This suggests that VP40 is a novel virulence determinant inducing distinct degrees of pro-inflammatory responses among ebolaviruses. Mechanistically, VP40 activated the NF-{kappa}B 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.
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