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Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis.

Blanc M, Hsieh WY, Robertson KA, Watterson S, Shui G, Lacaze P, Khondoker M, Dickinson P, Sing G, Rodríguez-Martín S, Phelan P, Forster T, Strobl B, Müller M, Riemersma R, Osborne T, Wenk MR, Angulo A, Ghazal P - PLoS Biol. (2011)

Bottom Line: Experimental testing of sterol metabolite levels using lipidomic-based measurements shows a reduction in metabolic output.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathway Medicine and Centre for Infectious Diseases, University of Edinburgh, Edinburgh, United Kingdom.

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 IFNγ or β but not TNF, IL1β, 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 IFNβ 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, IFNβ, 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 IFNβ 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.

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Proposed model for down-regulation of the sterol synthesis by type I interferon response to viral infection.
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pbio-1000598-g010: Proposed model for down-regulation of the sterol synthesis by type I interferon response to viral infection.

Mentions: Our results are consistent with a model involving a two-step interferon response for modulating endogenous sterol pathway activity upon infection. Figure 10 illustrates the two signaling cascades, a virus-induced interferon-producing signal and an interferon receptor-mediated secondary signal. The first is initiated by the detection of virion proteins and nucleic acids by host recognition receptors with the result of the infected cell producing type I interferon. As part of the second step all type I interferons bind to one common receptor (IFNAR1). The IFN-α/β receptor (IFNAR1) signals through the JAK/STAT pathway by phosphorylation of the Janus kinase (JAK)1, tyrosine kinase (Tyk)2, and signal transducer and activator of transcription (STAT)1 and STAT2, which subsequently modulates a diverse array of genes. In the case of mCMV the first step has been extensively investigated and shown to involve TLR2, TLR3, and TLR9 recognition receptors [54],[55], whose activation leads to the induction of transcription factors, NFkB, ATF2/c-Jun, and IRF3 that directly activate IFNα and β genes. Interestingly, previous studies [5],[37] have shown that microbial activation of TLR3 or TLR4 inhibits by an as-yet unknown mechanism LXR target genes such as ABCA1, resulting in the inhibition of cholesterol efflux from macrophages. This is reported to occur in a type I interferon-independent manner [5]. Similar to microbial-mediated TLR activation of IRF3, many viruses including mCMV potently induce IRF3 and may also have the potential to inhibit LXR functions. Despite recent progress in the definition of links between intracellular cholesterol homeostasis and innate immunity, little is known regarding the influence of interferon-regulated signaling on this phenomenon.


Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis.

Blanc M, Hsieh WY, Robertson KA, Watterson S, Shui G, Lacaze P, Khondoker M, Dickinson P, Sing G, Rodríguez-Martín S, Phelan P, Forster T, Strobl B, Müller M, Riemersma R, Osborne T, Wenk MR, Angulo A, Ghazal P - PLoS Biol. (2011)

Proposed model for down-regulation of the sterol synthesis by type I interferon response to viral infection.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3050939&req=5

pbio-1000598-g010: Proposed model for down-regulation of the sterol synthesis by type I interferon response to viral infection.
Mentions: Our results are consistent with a model involving a two-step interferon response for modulating endogenous sterol pathway activity upon infection. Figure 10 illustrates the two signaling cascades, a virus-induced interferon-producing signal and an interferon receptor-mediated secondary signal. The first is initiated by the detection of virion proteins and nucleic acids by host recognition receptors with the result of the infected cell producing type I interferon. As part of the second step all type I interferons bind to one common receptor (IFNAR1). The IFN-α/β receptor (IFNAR1) signals through the JAK/STAT pathway by phosphorylation of the Janus kinase (JAK)1, tyrosine kinase (Tyk)2, and signal transducer and activator of transcription (STAT)1 and STAT2, which subsequently modulates a diverse array of genes. In the case of mCMV the first step has been extensively investigated and shown to involve TLR2, TLR3, and TLR9 recognition receptors [54],[55], whose activation leads to the induction of transcription factors, NFkB, ATF2/c-Jun, and IRF3 that directly activate IFNα and β genes. Interestingly, previous studies [5],[37] have shown that microbial activation of TLR3 or TLR4 inhibits by an as-yet unknown mechanism LXR target genes such as ABCA1, resulting in the inhibition of cholesterol efflux from macrophages. This is reported to occur in a type I interferon-independent manner [5]. Similar to microbial-mediated TLR activation of IRF3, many viruses including mCMV potently induce IRF3 and may also have the potential to inhibit LXR functions. Despite recent progress in the definition of links between intracellular cholesterol homeostasis and innate immunity, little is known regarding the influence of interferon-regulated signaling on this phenomenon.

Bottom Line: Experimental testing of sterol metabolite levels using lipidomic-based measurements shows a reduction in metabolic output.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathway Medicine and Centre for Infectious Diseases, University of Edinburgh, Edinburgh, United Kingdom.

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 IFNγ or β but not TNF, IL1β, 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 IFNβ 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, IFNβ, 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 IFNβ 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.

Show MeSH
Related in: MedlinePlus