Release of cellular proteases into the acidic extracellular milieu exacerbates Ebola virus-induced cell damage

Ebola virus is highly cytopathic through mechanisms that are largely unknown. We present evidence that progressive acidification of the extracellular milieu by Ebola virus-infected cells combined with reduced levels of natural cysteine protease inhibitor makes the cells vulnerable to uncontrolled proteolysis of extracellular matrix components by released active endosomal cathepsins, thereby exacerbating Ebola virus-induced cell destruction. The cell surface microenvironment was shown to be crucial in aiding this activity. Blocking the proteolytic activity with the cathepsin inhibitor E64 resulted in remarkable improvements with respect to viral cytopathicity and cell survival despite an overwhelmingly high viral load. We propose that the observed enzymatic matrix degradation, enhanced by an associated protease/inhibitor imbalance and metabolic acidosis, represents an effective viral strategy to boost infection and underlies, in part, the remarkable pathogenesis caused by Ebola virus. Further in vitro and in vivo research will establish whether a cellular protease with hemorrhagic activity is the leading cause of vascular leakage-the hallmark of Ebola virus hemorrhagic fever-and help understand the Ebola virus caused cell death.