Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing

Abstract

Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013-2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD. Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.

Statins and the COVID-19 main protease: in silico evidence on direct interaction

“…Disruption of protease activity and decreased ratios of the mature glycoproteins to precursor form are possible mechanisms of the antiviral effect of statins. Disruption of the viral protease activity is an important therapeutic goal [16].…”

The axonal sorting activity of pseudorabies virus Us9 protein depends on the state of neuronal maturation

“…Together, these results suggest an inhibitory, anti-viral function for SMPD4 in PRV infection. A further test of the antiviral role of SMPD4 would be to know if the widely used statins, drugs that reduce cholesterol, affect the spread of PRV or other neurotropic viruses as it has been shown for Ebola (34).…”

Down regulation ofHmgcrin response to Influenza A infection is independent of the IFN response in human cells

“…The RNAi mediated knockdown of HMGCR protein levels and pharmaceutical inhibition of HMGCR activity down-regulates viral activity ( Figure 1) and have the potential to protect hosts from viral infection [1, [22][23][24][25]. Moreover, the inhibition of HMGCR increases the expression of interferon-responsive genes [26].…”

“…However, current data indicate that 25-HC does not play a major role in cholesterol homeostasis but instead has immune modulatory functions [3,8,9]. 25-HC has antiviral activity against several enveloped viruses by blocking viral entry by directly modifying membranes to inhibit membrane fusions [10]. It also has effects against non-enveloped viruses, including human papillomavirus-16 (HPV-16), human rotavirus (HRoV), and human rhinovirus (HRhV) [11].…”