Lipids and flaviviruses, present and future perspectives for the control of dengue, Zika, and West Nile viruses

Martín-Acebes, Miguel A.; Vázquez-Calvo, Ángela; Saiz, Juan-Carlos

doi:10.1016/j.plipres.2016.09.005

Cited by 124 publications

(107 citation statements)

References 174 publications

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“…Accordingly, pharmacological manipulation of cellular lipid metabolism is rising as an alternative potential strategy to combat these pathogens (7,8). Along these lines, we have shown that the hypolipidemic compound NDGA and its synthetic derivative M 4 N exhibit potent antiviral activity against WNV and ZIKV.…”

Section: Discussionmentioning

confidence: 99%

“…Recent advances have revealed that positive-stranded RNA viruses, including the flaviviruses, rearrange host cell lipid metabolism and coopt for cellular lipids to com-plete their life cycle (5)(6)(7). Considering this dependence on lipid metabolism during flavivirus infection, pharmacological modification of the lipid metabolic pathways appears to be a proper strategy to impair flaviviral replication (7,8).…”

mentioning

confidence: 99%

“…Considering this dependence on lipid metabolism during flavivirus infection, pharmacological modification of the lipid metabolic pathways appears to be a proper strategy to impair flaviviral replication (7,8). Along these lines, the hypolipidemic drug nordihydroguaiaretic acid (NDGA) has been reported to inhibit replication of the flavivirus DENV (9).…”

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confidence: 99%

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Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra- O -Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

Merino-Ramos

Oya

Saiz

et al. 2017

Antimicrob Agents Chemother

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Flaviviruses are positive-strand RNA viruses distributed all over the world that infect millions of people every year and for which no specific antiviral agents have been approved. These viruses include the mosquito-borne West Nile virus (WNV), which is responsible for outbreaks of meningitis and encephalitis. Considering that nordihydroguaiaretic acid (NDGA) has been previously shown to inhibit the multiplication of the related dengue virus and hepatitis C virus, we have evaluated the effect of NDGA, and its methylated derivative tetra-O-methyl nordihydroguaiaretic acid (M 4 N), on the infection of WNV. Both compounds inhibited the infection of WNV, likely by impairing viral replication. Since flavivirus multiplication is highly dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the sterol regulatory element-binding proteins (SREBP) pathway. Remarkably, we observed that other structurally unrelated inhibitors of the SREBP pathway, such as PF-429242 and fatostatin, also reduced WNV multiplication, supporting that the SREBP pathway may constitute a druggable target suitable for antiviral intervention against flavivirus infection. Moreover, treatment with NDGA, M 4 N, PF-429242, and fatostatin also inhibited the multiplication of the mosquito-borne flavivirus Zika virus (ZIKV), which has been recently associated with birth defects (microcephaly) and neurological disorders. Our results point to SREBP inhibitors, such as NDGA and M 4 N, as potential candidates for further antiviral development against medically relevant flaviviruses.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra- O -Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

Merino-Ramos

Oya

Saiz

et al. 2017

Antimicrob Agents Chemother

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“…DENV was also recently related to regulate the degradation of the host lipid droplet; it has been shown that a viral protein (NS4A) exploits the acyltransferase activity of AUP1, a lipid droplet‐localized type‐III membrane protein, to trigger lipophagy . In addition, some cholesterol uptake receptors, such as the low‐density lipoprotein receptor (LDLr), are known to participate during DENV infection, making it possible to identify the changes in lipid metabolism during DENV infection that can be used to develop new biomarkers of disease severity . However, the various studies showing the association between circulating lipid levels and the severity of dengue so far lack consistency .…”

Section: Introductionmentioning

confidence: 99%

Serum lipid profile as a predictor of dengue severity: A systematic review and meta‐analysis

Lima

Souza

Fernandes

et al. 2019

Reviews in Medical Virology

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Summary Dengue virus is known to modulate host cell lipid metabolism in order to promote efficient viral replication. Recent studies have focused on circulating lipids as potential biomarkers of dengue severity; however, the results obtained so far lack the consistency to establish a definite relationship between the two. Therefore, in the present study, we investigated serum lipids as potential biomarkers of dengue severity by conducting a meta‐analysis of the currently available clinical data. Nine studies that evaluated 1,953 patients were included in the review, many of which were cross‐sectional (44.4%) and conducted in Asian countries (55.5%). These studies observed the presence of lipids in serum samples (77%) of patients in the acute phase of the disease (88.8%). Circulating total‐cholesterol (P = .001) and LDL (P = .001) levels, but not HDL (P = .07), VLDL (P = .9) and triglyceride (P = .57) levels, were inversely and significantly correlated with dengue severity. Total cholesterol (P ≤ .001) and LDL (P = .001) were also useful in determining the risk of hypovolemic shock in patients with severe dengue. Subgroup analysis showed that factors, such as design (cross‐sectional vs cohort), racial‐ethnic differences (Asian vs Latin Americans), and age range (children vs adult) influenced the correlation and also contributed to the high level of heterogeneity in the studies. Our meta‐analysis demonstrates that total‐cholesterol and LDL‐cholesterol levels should be explored as routine laboratory markers for dengue severity, as they will help in employing an appropriate patient therapy, and thus optimize the use of available resources.

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“…40,41 Likewise, the involvement of neutral sphingomyelinase in USUV infection has unveiled a connection between sphingomyelin metabolism and USUV biogenesis. 42,43 Moreover, infection with USUV triggered an autophagic response in the host cell ( Figure 4). 44 Autophagy is an important cellular pathway that plays important roles in viral infections and pathogenesis, and the upregulation of the autophagic pathway has been well documented for various flaviviruses, 45 although the involvement of autophagy in WNV infection is still controversial.…”

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confidence: 99%

Usutu virus: current knowledge and future perspectives

Saiz¹,

Blázquez²

2017

VAAT

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Abstract:The Flavivirus genus (Flaviviridae family) contains important pathogens such as yellow fever virus, Japanese encephalitis virus, St Louis encephalitis virus, West Nile virus, Usutu virus (USUV), Zika virus, and dengue virus, many of which constitute a worrisome threat to global human and animal health. USUV is transmitted by mosquitoes and, as any other flavivirus, is an enveloped plus-strand RNA virus. The virus was first isolated from Culex neavei mosquitoes in South Africa in 1959 near the Usutu River, from where it takes its name. Since then, the virus was confined to Africa until its first detection in Austria in 2001, although it was probably present in Europe since 1996 or even earlier. After that, USUV has spread throughout Europe, causing a considerable mortality among birds and a few neurologic cases in humans. The main USUV natural hosts are birds, but infection has also been reported in other vertebrate species, including humans. The fast spread of the virus through the continent, the relatively high mortality caused in birds, and the recent neuroinvasive human cases related to USUV infection reported in Europe have raised serious concerns about its possible consequences for public health. Here, an updated review of current knowledge about this emerging pathogen is presented. Keywords: Usutu virus, flavivirus, host cell-virus interactions, surveillance, prophylaxis Biology of the virus Molecular classification and phylogenyUsutu virus (USUV) is a member of the Flavivirus genus within the Flaviviridae family ( Figure 1A). In 2004, the complete genomic sequences of two USUV strains, one African (South Africa-1959) and one European (Vienna-2001), were used to build a phylogenetic tree. These two strains showed a 97% and 99% homology at the nucleotide (nt) and amino acid (aa) level, respectively.1 Both strains were closely related to Murray valley encephalitis virus (73% and 82% nt and aa similarity), Japanese encephalitis virus (71% and 81% nt and aa similarity), and to West Nile virus (WNV; 68% and 75% nt and aa similarity). Nowadays, dozens of complete sequences are available in the data banks. In a recent study, the sequence identity among seven USUV strains was 96%-99% and 99% at the nt and aa levels, respectively.2 The only exception was a 1969 isolate from Central African Republic (CAR-1969) that presented homologies of 81% and 94% at the nt and aa levels with other African sequences ( Figure 1B). Due to these differences, it has been suggested that CAR-1969 formed an USUV subtype strain.3 A comparison with the original South African SAAR-1776 strain showed that the mutations found among different European and African strains were scattered throughout the genome, with some unique substitutions and some that were present

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Lipids and flaviviruses, present and future perspectives for the control of dengue, Zika, and West Nile viruses

Cited by 124 publications

References 174 publications

Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra- O -Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra- O -Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

Serum lipid profile as a predictor of dengue severity: A systematic review and meta‐analysis

Usutu virus: current knowledge and future perspectives

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