Ghazal, Peter

Riemersma, Rudolph

Blanc, Mathieu

British Heart Foundation

Wellcome Trust

2011-10-10T14:29:42Z

2011-10-10T14:29:42Z

2011-06-27

Recently, cholesterol metabolism has been shown to modulate the infection of several viruses and there is growing evidence that inflammatory response to infection also modulates lipid metabolism. However little is known about the role of inflammatory processes in modulating lipid metabolism and their consequences for the viral infection. This study investigates host-lipid viral interaction pathways using mouse cytomegalovirus, a large double-stranded DNA genome, which represents one of the few models for a natural infection of its natural host. In this study, transcriptomic and lipidomic profiling of macrophages shows that there is a specific coordinated regulation of the sterol pathways upon viral infection or treatment with IFNγ or β (but not TNFα, IL1β or IL6) resulting in the decrease of free cellular cholesterol. Furthermore, we show that pharmacological and RNAi inhibition of the sterol pathway augments protection against infection in vitro and in vivo and we identified that the prenylation branch of the sterol metabolic network was involved in the protective response. Finally, we show that genetic knock out of IFNβ results in a partial reduction while genetic knock out of Ifnar1 completely abolishes the reduction of the sterol biosynthetic activity upon infection. Overall these results support a role for part of the sterol metabolic network in protective immunity and show that type 1 IFN signalling is both necessary and sufficient for reducing the sterol metabolic network upon infection; thereby linking the sterol pathway with IFN defence responses.

http://hdl.handle.net/1842/5556

en

The University of Edinburgh

cholesterol

infection

interference

immune response

CMV

interferon

Sterol biosynthesis pathway is part of the interferon host defence response

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy