PT - JOURNAL ARTICLE AU - Nitish Boodhoo AU - Nitin Kamble AU - Benedikt B. Kaufer AU - Shahriar Behboudi TI - Targeted induction of <em>de novo</em> Fatty acid synthesis enhances MDV replication in a COX-2/PGE<sub>2α</sub> dependent mechanism through EP2 and EP4 receptors engagement AID - 10.1101/323840 DP - 2018 Jan 01 TA - bioRxiv PG - 323840 4099 - http://biorxiv.org/content/early/2018/05/16/323840.short 4100 - http://biorxiv.org/content/early/2018/05/16/323840.full AB - 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. Marek’s 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/PGE2α pathway and increases the biosynthesis of PGE2α, a lipid mediator generated from arachidonic acid. Inhibition of COX-2 or PGE2α receptors, namely EP2 and EP4 receptors, reduced MDV titer, indicating that COX-2/PGE2α pathway are involved in virus replication. Our data show that the FA synthesis pathway inhibitors reduce COX-2 expression level and PGE2α synthesis in MDV infected cells, arguing that there is a direct link between virus-induced fatty acid synthesis and activation of COX-2/PGE2α pathway. This notion was confirmed by the results showing that PGE2α 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 PGE2α synthesis and promote MDV replication through EP2 and EP4 receptors engagement.