Cholesterol biosynthesis modulation regulates dengue viral replication.
We performed a focused siRNA screen in an A549 dengue type 2 New Guinea C subgenomic replicon cell line (Rluc-replicon) that contains a Renilla luciferase cassette. We found that siRNA mediated knock down of mevalonate diphospho decarboxylase (MVD) inhibited viral replication of the Rluc-replicon and DEN-2 NGC live virus replication in A549 cells. When the Rluc-replicon A459 cells were grown in delipidated media the replicon expression was suppressed and MVD knock down could further sensitize Renilla expression. Hymeglusin and zaragozic acid A could inhibit DEN-2 NGC live virus replication in K562 cells, while lovastatin could inhibit DEN-2 NGC live virus replication in human peripheral blood mononuclear cells. Renilla expression could be rescued in fluvastatin treated A549 Rluc-replicon cells after the addition of mevalonate, and partially restored with geranylgeranyl pyrophosphate, or farnesyl pyrophosphate. Our data suggest genetic and pharmacological modulation of cholesterol biosynthesis can regulate dengue virus replication.
Novartis Institutes for Biomedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, USA.
Christopher
C
Rothwell
Aude
A
Lebreton
Chuan
C
Young Ng
Joanne Y H
JY
Lim
Wei
W
Liu
Subhash
S
Vasudevan
Mark
M
Labow
Feng
F
Gu
L Alex
LA
Gaither
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D003716:Dengue Virus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D055785:Gene Knockdown Techniques; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020014:K562 Cells; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D012093:Replicon / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology; D014233:Tricarboxylic Acids / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011106:Polyisoprenyl Phosphates; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D000077340:Fluvastatin; C004808:farnesyl pyrophosphate; D002784:Cholesterol; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid