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

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

Abstract

Little is known about the protective role of inflammatory processes in modulating lipid metabolism in infection. Here we report an intimate link between the innate immune response to infection and regulation of the sterol metabolic network characterized by down-regulation of sterol biosynthesis by an interferon regulatory loop mechanism. In time-series experiments profiling genome-wide lipid-associated gene expression of macrophages, we show a selective and coordinated negative regulation of the complete sterol pathway upon viral infection or cytokine treatment with IFNc or b but not TNF, IL1b, or IL6. Quantitative analysis at the protein level of selected sterol metabolic enzymes upon infection shows a similar level of suppression. Experimental testing of sterol metabolite levels using lipidomic-based measurements shows a reduction in metabolic output. On the basis of pharmacologic and RNAi inhibition of the sterol pathway we show augmented protection against viral infection, and in combination with metabolite rescue experiments, we identify the requirement of the mevalonate-isoprenoid branch of the sterol metabolic network in the protective response upon statin or IFNb treatment. Conditioned media experiments from infected cells support an involvement of secreted type 1 interferon(s) to be sufficient for reducing the sterol pathway upon infection. Moreover, we show that infection of primary macrophages containing a genetic knockout of the major type I interferon, IFNb, leads to only a partial suppression of the sterol pathway, while genetic knockout of the receptor for all type I interferon family members, ifnar1, or associated signaling component, tyk2, completely abolishes the reduction of the sterol biosynthetic activity upon infection. Levels of the proteolytically cleaved nuclear forms of SREBP2, a key transcriptional regulator of sterol biosynthesis, are reduced upon infection and IFNb treatment at both the protein and de novo transcription level. The reduction in srebf2 gene transcription upon infection and IFN treatment is also found to be strictly dependent on ifnar1. Altogether these results show that type 1 IFN signaling is both necessary and sufficient for reducing the sterol metabolic network activity upon infection, thereby linking the regulation of the sterol pathway with interferon anti-viral defense responses. These findings bring a new link between sterol metabolism and interferon antiviral response and support the idea of using host metabolic modifiers of innate immunity as a potential antiviral strategy.

Citation

Blanc, M., Yuan Hsieh, W., Robertson, K. A., Watterson, S., Shui, G., Lacaze, P., Khondoker, M., Dickinson, P., Sing, G., Rodríguez-Martín, S., Phelan, P., Forster, T., Strobl, B., Mü Ller, M., Riemersma, R., Osborne, T., Wenk, M. R., Angulo, A., & Ghazal, P. (2011). Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis. PLOS Biology, 9(3), Article e1000598. https://doi.org/10.1371/journal.pbio.1000598

• Journal Article Type: Article
• Online Publication Date: Mar 8, 2011
• Publication Date: 2011
• Deposit Date: Feb 14, 2025
• Publicly Available Date: Feb 14, 2025
• Journal: PLoS Biology
• Print ISSN: 1545-7885
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 3
• Article Number: e1000598
• DOI: https://doi.org/10.1371/journal.pbio.1000598
• Keywords: Abbreviations: CMV, cytomegalovirus; Fdps, farnesyl diphosphate synthase; HCV, Hepatitis C virus; hpi, hours post-infection; HSV1, herpes simplex virus 1; IFN, interferon; IFNAR1, IFN-a/b receptor; JAK, Janus kinase; LAG, Lipid Associated Gene; mCMV, murine cytomegalovirus; MRM, multiple reaction monitoring; PRR, host recognition receptor; SREBP2, sterol regulatory binding protein 2; STAT, signal transducer and activator of transcription; Tyk 2
• Public URL: http://researchrepository.napier.ac.uk/Output/4119415