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bioRxiv · 10.1101/323840

Targeted induction of de novo Fatty acid synthesis enhances MDV replication in a COX-2/PGE2 dependent mechanism through EP2 and EP4 receptors engagement

Boodhoo, N.·Kamble, N.·Kaufer, B.·Behboudi, S.
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Abstract

Many viruses alter de novo Fatty Acid (FA) synthesis pathway, which can increase availability of energy for replication and provide specific cellular substrates for particle assembly. Mareks disease virus (MDV) is a herpesvirus that causes deadly lymphoma and has been linked to alterations of lipid metabolism in MDV-infected chickens. However, the role of lipid metabolism in MDV replication is largely unknown. We demonstrate here that infection of primary chicken embryonic fibroblast with MDV activates de novo lipogenesis, which is required for virus replication. In contrast, activation of Fatty Acid Oxidation (FAO) reduced MDV titer, while inhibition of FAO moderately increased virus replication. Thus optimized virus replication occurs if synthetized fatty acids are not used for generation of energy in the infected cells, and they are likely converted to lipid compounds, which are important for virus replication. We showed that infection with MDV activates COX-2/PGE2 pathway and increases the biosynthesis of PGE2, a lipid mediator generated from arachidonic acid. Inhibition of COX-2 or PGE2 receptors, namely EP2 and EP4 receptors, reduced MDV titer, indicating that COX-2/PGE2 pathway are involved in virus replication. Our data show that the FA synthesis pathway inhibitors reduce COX-2 expression level and PGE2 synthesis in MDV infected cells, arguing that there is a direct link between virus-induced fatty acid synthesis and activation of COX-2/PGE2 pathway. This notion was confirmed by the results showing that PGE2 can restore MDV replication in the presence of the FA synthesis pathway inhibitors. Taken together, our data demonstrate that MDV uses FA synthesis pathway to enhance PGE2 synthesis and promote MDV replication through EP2 and EP4 receptors engagement.

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Boodhoo, N., Kamble, N., Kaufer, B., Behboudi, S.. 2018-05-16. Targeted induction of de novo Fatty acid synthesis enhances MDV replication in a COX-2/PGE2 dependent mechanism through EP2 and EP4 receptors engagement. https://doi.org/10.1101/323840

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