title: Inhibition of rotavirus replication by downregulation of fatty acid synthesis.
abstract: Recently the recruitment of lipid droplets (LDs) to sites of rotavirus (RV) replication was reported. LDs are polymorphic organelles that store triacylglycerols, cholesterol and cholesterol esters. The neutral fats are derived from palmitoyl-CoA, synthesized via the fatty acid biosynthetic pathway. RV-infected cells were treated with chemical inhibitors of the fatty acid biosynthetic pathway, and the effects on viral replication kinetics were assessed. Treatment with compound C75, an inhibitor of the fatty acid synthase enzyme complex (FASN), reduced RV infectivity 3.2-fold (P = 0.07) and modestly reduced viral RNA synthesis (1.2-fold). Acting earlier in the fatty acid synthesis pathway, TOFA [5-(Tetradecyloxy)-2-furoic acid] inhibits the enzyme acetyl-CoA carboxylase 1 (ACC1). TOFA reduced the infectivity of progeny RV 31-fold and viral RNA production 6-fold. The effect of TOFA on RV infectivity and RNA replication was dose-dependent, and infectivity was reduced by administering TOFA up to 4 h post-infection. Co-treatment of RV-infected cells with C75 and TOFA synergistically reduced viral infectivity. Knockdown by siRNA of FASN and ACC1 produced findings similar to those observed by inhibiting these proteins with the chemical compounds. Inhibition of fatty acid synthesis using a range of approaches uniformly had a more marked impact on viral infectivity than on viral RNA yield, inferring a role for LDs in virus assembly and/or egress. Specific inhibitors of fatty acid metabolism may help pinpoint the critical structural and biochemical features of LDs that are essential for RV replication, and facilitate the development of antiviral therapies.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Eleanor R
authors.initials: ER
authors.lastname: Gaunt
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Winsome
authors.initials: W
authors.lastname: Cheung
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Richards
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lever
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Desselberger
mesh_terms: D053898:Biosynthetic Pathways / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D006801:Humans; D015388:Organelles / Q000378:metabolism; D012401:Rotavirus / Q000235:genetics / Q000502:physiology*; D012400:Rotavirus Infections / Q000201:enzymology / Q000378:metabolism / Q000821:virology*; D014779:Virus Replication
chemical_list: D004791:Enzyme Inhibitors; D005227:Fatty Acids; D064429:Fatty Acid Synthases