LXR Ligand GW3965 Inhibits Newcastle Disease Virus Infection By Affecting Choleserol Homeostasis

Newcastle disease(ND)is an acute,febrile and highly contagious disease caused by Newcastle disease virus.It happens all over the world and will result in a great economical loss in the poultry industry.Since its discovery in 1926,ND has struck four times in the world.The world organization for animal health(OIE)classified it as a category A infectious diseases.Newcastle disease virus(NDV),the causative agent of Newcastle disease(ND),can infect at least 241 species of birds and result in a substantial economic loss to the poultry industry.Newcastle disease virus is an enveloped,non-segmented,negative-stranded RNA virus,belonging to Paramyxoviridae family.The genome of NDV encodes six structural proteins,including nucleoprotein(NP),phosphoprotein(P),large polymerase protein(L),matrix protein(M),hemagglutinin-neuraminidase(HN),and fusion(F)glycoprotein.Although routinely vaccinated with live NDV vaccines,Newcastle disease remains a severe burden for poultry production.Viruses can hijack host machinery for their own benefit;lipid metabolism is one of the features that the viruses employ.Infection of NDV can disturb the lipid metabolism in chickens.Studies on various viruses demonstrated that pharmacological agents targeting lipid metabolism can inhibit the infection.Liver X receptors(LXRs)belong to the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of lipid homeostasis.It has two isoforms,LXR-?and LXR-?.LXRs regulate cholesterol and lipid metabolism;LXR target genes ABCA1 promote the efflux of cellular cholesterol to maintain sterol homeostasis.Cholesterol modulates the properties of lipid bilayers.It is the major component of lipid rafts,the platform that signaling molecule complexes assemble.Lipid rafts are required for the entry of a number of viruses,including severe acute respiratory syndrome(SARS)and Japanese encephalitis virus.GW3965 is a widely used agonist of LXR,it can effectively stimulate LXR and its downstream gene expression,including ABCA1(ATP combination box transporter A1).ABCA1 is a regulator of cholesterol metabolism,which mediates the transport of cholesterol,phospholipids,and other metabolites from cells to lipid-depleted HDL apolipoproteins.Related studies show that many viruses infection will take advantage of the host cell cholesterol and cholesterol reagents can obviously reduce virus infection.In our studies,we showed that LXR ligand,GW3965,inhibited Newcastle disease virus(NDV)infection.GW3965 inhibited NDV-induced NF-?B activation and decreased the upregulation of proinflammatory cytokines during the infection.GW3965 exerted its inhibitory effect at virus entry and virus replication.Meanwhile,NDV infection impaired ABCA1 expression.GW3965 treatment restored ABCA1 gene expression during NDV infection.Overexpression ABCA1 reduced NDV infection and attenuated the cholesterol accumulation in infected cells,which might affect NDV entry,viral genome replication,assembly,and budding.