Cholesterol manipulation by West Nile virus perturbs the cellular immune response

Complex membrane structures induced by West Nile virus (WNV), an enveloped RNA virus, are required for efficient viral replication. How these membranes are induced and how they facilitate the viral life cycle are unknown. We show that WNV modulates host cell cholesterol homeostasis by upregulating c...

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Published in	Cell host & microbe Vol. 2; no. 4; pp. 229 - 239
Main Authors	Mackenzie, Jason M, Khromykh, Alexander A, Parton, Robert G
Format	Journal Article
Language	English
Published	United States 01.10.2007
Subjects	Animals Cell Line, Tumor Cercopithecus aethiops Cholesterol - metabolism Down-Regulation Homeostasis - drug effects Humans Hydroxymethylglutaryl CoA Reductases - metabolism Interferon-alpha - metabolism Janus Kinase 1 - metabolism STAT Transcription Factors - metabolism Vero Cells Virus Replication West Nile Fever - immunology West Nile Fever - metabolism West Nile Fever - virology West Nile virus West Nile virus - physiology
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Abstract	Complex membrane structures induced by West Nile virus (WNV), an enveloped RNA virus, are required for efficient viral replication. How these membranes are induced and how they facilitate the viral life cycle are unknown. We show that WNV modulates host cell cholesterol homeostasis by upregulating cholesterol biosynthesis and redistributing cholesterol to viral replication membranes. Manipulating cholesterol levels and altering concentrations of cellular geranylgeranylated proteins had a deleterious effect on virus replication. Depletion of the key cholesterol-synthesizing enzyme 3-hydroxy-methyglutaryl-CoA reductase drastically hampered virus replication. Significantly, virus-induced redistribution of cellular cholesterol downregulated the interferon-stimulated Jak-STAT antiviral signaling response to infection. This defect could be partially restored by exogenous addition of cholesterol, which increased the ability of infected cells to respond to interferon. We propose that, by manipulating cellular cholesterol, WNV utilizes the cellular response to cholesterol deficiency and dependence of antiviral signaling pathways on cholesterol-rich microdomains to facilitate viral replication and survival.
AbstractList	Complex membrane structures induced by West Nile virus (WNV), an enveloped RNA virus, are required for efficient viral replication. How these membranes are induced and how they facilitate the viral life cycle are unknown. We show that WNV modulates host cell cholesterol homeostasis by upregulating cholesterol biosynthesis and redistributing cholesterol to viral replication membranes. Manipulating cholesterol levels and altering concentrations of cellular geranylgeranylated proteins had a deleterious effect on virus replication. Depletion of the key cholesterol-synthesizing enzyme 3-hydroxy-methyglutaryl-CoA reductase drastically hampered virus replication. Significantly, virus-induced redistribution of cellular cholesterol downregulated the interferon-stimulated Jak-STAT antiviral signaling response to infection. This defect could be partially restored by exogenous addition of cholesterol, which increased the ability of infected cells to respond to interferon. We propose that, by manipulating cellular cholesterol, WNV utilizes the cellular response to cholesterol deficiency and dependence of antiviral signaling pathways on cholesterol-rich microdomains to facilitate viral replication and survival.
Author	Parton, Robert G Khromykh, Alexander A Mackenzie, Jason M
Author_xml	– sequence: 1 givenname: Jason M surname: Mackenzie fullname: Mackenzie, Jason M email: j.mackenzie@uq.edu.au organization: School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland 4072, Australia. j.mackenzie@uq.edu.au – sequence: 2 givenname: Alexander A surname: Khromykh fullname: Khromykh, Alexander A – sequence: 3 givenname: Robert G surname: Parton fullname: Parton, Robert G
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/18005741$$D View this record in MEDLINE/PubMed
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Snippet	Complex membrane structures induced by West Nile virus (WNV), an enveloped RNA virus, are required for efficient viral replication. How these membranes are...
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SubjectTerms	Animals Cell Line, Tumor Cercopithecus aethiops Cholesterol - metabolism Down-Regulation Homeostasis - drug effects Humans Hydroxymethylglutaryl CoA Reductases - metabolism Interferon-alpha - metabolism Janus Kinase 1 - metabolism STAT Transcription Factors - metabolism Vero Cells Virus Replication West Nile Fever - immunology West Nile Fever - metabolism West Nile Fever - virology West Nile virus West Nile virus - physiology
Title	Cholesterol manipulation by West Nile virus perturbs the cellular immune response
URI	https://www.ncbi.nlm.nih.gov/pubmed/18005741 https://search.proquest.com/docview/19603763 https://search.proquest.com/docview/68510552
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