Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis

Mathieu Blanc,Thorsten Forster,Matthias Müller,Rudolph Riemersma,Steven Watterson,Mizanur Khondoker,Paul Lacaze,Ana Angulo,Timothy Osborne,Guanghou Shui,Garwin Sing,Birgit Strobl,Wei Yuan Hsieh,Peter Ghazal,Peter Phelan,Markus R Wenk,Sara Rodríguez-Martín,Kevin A Robertson,Paul Dickinson

doi:10.1371/journal.pbio.1000598

Abstract

Author SummaryCurrently, little is known about the crosstalk between the body's immune and metabolic systems that occurs after viral infection. This work uncovers a previously unappreciated physiological role for the cholesterol-metabolic pathway in protecting against infection that involves a molecular link with the protein interferon, which is made by immune cells and known to “interfere” with viral replication. We used a clinically relevant model based on mouse cytomegalovirus (CMV) infection of bone-marrow-derived cells. Upon infection these cells produce high levels of interferon as part of the innate-immune response, which we show in turn signals through the interferon receptor resulting in lowering enzyme levels on the cholesterol pathway. We observed this effect with a range of other viruses, and in each case it leads to a notable drop in the metabolites involved in the cholesterol pathway. We found that the control mechanism involves regulation by interferon of an essential transcription factor, named SREBP-2, which coordinates the gene activity of the cholesterol pathway. This mechanism may explain clinical observations of reduced cholesterol levels in patients receiving interferon treatment. Our initial investigation into how lowered cholesterol might protect against viral infection reveals that the protection is not due to a requirement of the virus for cholesterol itself but instead involves a particular side-branch of the pathway that chemically links lipids to proteins. Drugs such as statins and small interfering RNAs that block this part of the pathway are also shown to protect against CMV infection of cells in culture and in mice. This provides the first example of targeting a host metabolic pathway in order to protect against an acute infection.

Highlights

Sterols and fatty acids are common intermediary metabolites that play key roles in many biological pathways involved in inflammatory diseases such as atherosclerosis and chronic heart disease [1,2,3,4]
We found that the control mechanism involves regulation by interferon of an essential transcription factor, named SREBP-2, which coordinates the gene activity of the cholesterol pathway
A definitive link to sterol metabolism that is independent of cholesterol is established by the observation that the anti-viral effect of down-regulating the sterol pathway upon infection is completely blocked if cells are provided with an excess of mevalonate but not cholesterol

Summary

Introduction

Sterols and fatty acids are common intermediary metabolites that play key roles in many biological pathways involved in inflammatory diseases such as atherosclerosis and chronic heart disease [1,2,3,4]. We used a clinically relevant model based on mouse cytomegalovirus (CMV) infection of bone-marrowderived cells Upon infection these cells produce high levels of interferon as part of the innate-immune response, which we show in turn signals through the interferon receptor resulting in lowering enzyme levels on the cholesterol pathway. Our initial investigation into how lowered cholesterol might protect against viral infection reveals that the protection is not due to a requirement of the virus for cholesterol itself but instead involves a particular side-branch of the pathway that chemically links lipids to proteins Drugs such as statins and small interfering RNAs that block this part of the pathway are shown to protect against CMV infection of cells in culture and in mice. This provides the first example of targeting a host metabolic pathway in order to protect against an acute infection

Methods

Results

Conclusion