Abstract
ABSTRACTGammaherpesviruses are oncogenic pathogens that persist in ~95% of the adult population. Cellular metabolic pathways have emerged as important regulators of many viral infections, including infections by gammaherpesviruses that require several lipid synthetic pathways for optimal replication. Liver X receptors (LXRs) are transcription factors that are critical regulators of cellular fatty acid and cholesterol synthesis pathways. Not surprisingly, LXRs are attractive therapeutic targets in cardiovascular disease. Here we describe an antiviral role for LXRs in the context of gammaherpesvirus infection of primary macrophages. We show that type I interferon increased LXR expression following infection. Surprisingly, there was not a corresponding induction of LXR target genes. Rather, LXRs suppressed the expression of target genes, leading to decreased fatty acid and cholesterol synthesis, two metabolic pathways that support gammaherpesvirus replication. This report defines LXR-mediated restriction of cholesterol and lipid synthesis as an intrinsic metabolic mechanism to restrict viral replication in innate immune cells.
Highlights
Gammaherpesviruses are oncogenic pathogens that persist in ~95% of the adult population
We have shown that the related murine gammaherpesvirus 68 (MHV68) usurps intermediates of the cholesterol synthesis pathway to facilitate viral replication [13]
To define the role of Liver X receptors (LXRs) during MHV68 infection, viral replication was assessed in primary macrophages derived from C57BL/6J (BL6) mice or mice genetically deficient in both LXR␣ and LXR isoforms [16]
Summary
Gammaherpesviruses are oncogenic pathogens that persist in ~95% of the adult population. Liver X receptors (LXRs) are transcription factors that are critical regulators of cellular fatty acid and cholesterol synthesis pathways. LXRs suppressed the expression of target genes, leading to decreased fatty acid and cholesterol synthesis, two metabolic pathways that support gammaherpesvirus replication. This report defines LXR-mediated restriction of cholesterol and lipid synthesis as an intrinsic metabolic mechanism to restrict viral replication in innate immune cells. IMPORTANCE Fatty acid and cholesterol synthesis pathways of the host play important roles in diverse biological systems. These two metabolic pathways are usurped by a number of viruses to facilitate viral replication. Consistent with the role of LXRs as metabolic regulators, most LXR target genes encode proteins that mediate fatty acid synthesis or cholesterol efflux from cells. Increased fatty acid synthesis induced by treatment with synthetic LXR agonists facilitates replication of coxsackie B virus [2]
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