The Role of Host Cholesterol During Flavivirus Infection

Abstract

In recent years the emergence and resurgence of arboviruses have generated a global health alert. Among arboviruses, Dengue (DENV), Zika (ZIKV), Yellow Fever (YFV), and West Nile (WNV) virus, belong to the genus Flavivirus, cause high viremia and occasionally fatal clinical disease in humans. Given the genetic austerity of the virus, they depend on cellular factors and organelles to complete its replication. One of the cellular components required for flavivirus infection is cholesterol. Cholesterol is an abundant lipid in biomembranes of eukaryotes cells and is necessary to maintain the cellular homeostasis. Recently, it has been reported, that cholesterol is fundamental during flavivirus infection in both mammal and insect vector models. During infection with DENV, ZIKV, YFV, and WNV the modulation of levels of host-cholesterol facilitates viral entry, replicative complexes formation, assembly, egress, and control of the interferon type I response. This modulation involves changes in cholesterol uptake with the concomitant regulation of cholesterol receptors as well as changes in cholesterol synthesis related to important modifications in cellular metabolism pathways. In view of the flavivirus dependence of cholesterol and the lack of an effective anti-flaviviral treatment, this cellular lipid has been proposed as a therapeutic target to treat infection using FDA-approved cholesterol-lowering drugs. This review aims to address the dependence of cholesterol by flaviviruses as well as the basis for anti flaviviral therapy using drugs which target is cholesterol synthesis or uptake.

Modulation of cell proteome by 25-hydroxycholesterol and 27-hydroxycholesterol: A link between cholesterol metabolism and antiviral defense

“…For instance, both investigated oxysterols strongly down-regulated cellular levels of hydroxymethylglutaryl-CoA (HMG-CoA) synthase, the key regulatory enzyme of the cholesterol synthetic pathway. This is consistent with previous literature, showing that 25-HC is a HMG-CoA reductase and synthase inhibitor [31] and, by means of this mechanism, it conveys an antiviral state in treated cells, particularly against flaviviruses, including hepatitits C virus [32]. Moreover, both oxysterols can downregulate the expression of isopentenyl-diphosphate delta-isomerase 1, a crucial regulatory enzyme in the synthesis of isoprenoids.…”

“…Peptides were separated using a 90 min linear gradient (from 1% acetonitrile, 0.1% formic acid to 40% acetonitrile, 0.1% formic acid) and on-line electrosprayed into an LTQ Orbitrap XL mass spectrometer equipped with a nanospray ion source (both Thermo). The mass spectrometer operated in data dependent acquisition (DDA) mode, controlled by the software Xcalibur (version 2.0.7, Thermo) to acquire both full MS spectra in the m/z range 320-1400 (resolution 1 × 10 5 FWHM at m/z 400) and MS/MS spectra obtained by collision induced dissociation [30][31][32][33][34][35][36] (CID) of the 6 most abundant multi-charged ions. Automatic gain control (AUG) was set at 1 × 10 6 for the acquisition of full MS spectra and at 1 × 10 5 for MS/MS spectra.…”

“…Quality filters were applied to focus on genuine identifications and quantifications. [30][31][32][33][34][35][36] Proteins modulated by 25HC and 27HC were detected by applying 5th and 95th percentile thresholds at the distribution of SILAC ratio obtained in each sample.…”

“…It must be outlined the fact that Sortilin-1 was not among the proteins whose cellular level was diminished by the oxysterol treatment, thus a MPRci independent Golgi-LE pathway may compensate the [30][31][32][33][34][35][36] specific decrease of a given transporter [41]. However, an actual coinvolvement of oxysterol-induced deficit of cell MPRci in the protective effect of 25HC and 27HC against rotavirus infection [5,6] could be reinforced by the evidence that defined rotavirus strains, including the human ones, utilize the tight junction protein JAM-A as a co-receptor to enter enterocyte cells [42].…”

Bafilomycin A1 and U18666A Efficiently Impair ZIKV Infection

“…There are reports describing the impact of U18666A on the replication of flaviviruses, such as HCV and DENV. Although there are differences in the structural organization of the replication factories and the formation of a membranous web structure, there seems to be parallels that make them accessible for an inhibition by U18666A [45][46][47].…”