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.