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) dur...

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Autores principales:	Punya Shrivastava-Ranjan, Mike Flint, Éric Bergeron, Anita K. McElroy, Payel Chatterjee, César G. Albariño, Stuart T. Nichol, Christina F. Spiropoulou
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Ebola virus Filoviridae antiviral hemorrhagic fever Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/eb5a3a1b6f3145578abdd9b3d291c4b9
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spelling	oai:doaj.org-article:eb5a3a1b6f3145578abdd9b3d291c4b92021-11-15T16:00:25ZStatins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing10.1128/mBio.00660-182150-7511https://doaj.org/article/eb5a3a1b6f3145578abdd9b3d291c4b92018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00660-18https://doaj.org/toc/2150-7511ABSTRACT 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 in vitro. 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. IMPORTANCE 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.Punya Shrivastava-RanjanMike FlintÉric BergeronAnita K. McElroyPayel ChatterjeeCésar G. AlbariñoStuart T. NicholChristina F. SpiropoulouAmerican Society for MicrobiologyarticleEbola virusFiloviridaeantiviralhemorrhagic feverMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Ebola virus Filoviridae antiviral hemorrhagic fever Microbiology QR1-502
spellingShingle	Ebola virus Filoviridae antiviral hemorrhagic fever Microbiology QR1-502 Punya Shrivastava-Ranjan Mike Flint Éric Bergeron Anita K. McElroy Payel Chatterjee César G. Albariño Stuart T. Nichol Christina F. Spiropoulou Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing
description	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 in vitro. 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. IMPORTANCE 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.
format	article
author	Punya Shrivastava-Ranjan Mike Flint Éric Bergeron Anita K. McElroy Payel Chatterjee César G. Albariño Stuart T. Nichol Christina F. Spiropoulou
author_facet	Punya Shrivastava-Ranjan Mike Flint Éric Bergeron Anita K. McElroy Payel Chatterjee César G. Albariño Stuart T. Nichol Christina F. Spiropoulou
author_sort	Punya Shrivastava-Ranjan
title	Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing
title_short	Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing
title_full	Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing
title_fullStr	Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing
title_full_unstemmed	Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing
title_sort	statins suppress ebola virus infectivity by interfering with glycoprotein processing
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/eb5a3a1b6f3145578abdd9b3d291c4b9
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Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing

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