Requirement of cholesterol in the viral envelope for dengue virus infection

Carro, Ana Clara; Damonte, Elsa B.

doi:10.1016/j.virusres.2013.03.005

Cited by 87 publications

(81 citation statements)

References 48 publications

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“…U18666A, an inhibitor of cholesterol synthesis and trafficking that has been reported to inhibit DENV in cell culture (25), was found in our screen to have anti-DENV-2 activity. Consistent with previous reports documenting the importance of fatty acid synthesis and metabolism in the DENV infectious cycle (25)(26)(27), a fatty acid synthesis inhibitor (5-(tetradecyloxy)-2-furoic acid [TOFA]) and an inhibitor of lipid catabolism (17-octadecynoic acid ) were active in our screen. DENV-2 was also sensitive to an inhibitor of protein geranylgeranylation (GGTI 297) and to several signal-transducing bioactive lipids, including 25-hydroxyvitamin D 3 , a prehormone, and arachidonamide, a synthetic analog of arachidonic acid and weak agonist of cannabinoid receptors.…”

Section: Resultssupporting

confidence: 91%

The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

Carocci

Hinshaw

Rodgers

et al. 2015

Antimicrob Agents Chemother

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Dengue virus (DENV) is a mosquito-borne pathogen that is the causative agent of dengue fever. Severe dengue virus infection is potentially fatal due to hemorrhaging, plasma leakage, and pulmonary shock. The four serotypes of DENV (DENV-1 to DENV-4) are defined by antigenic differences on the viral envelope protein, E, and together, they comprise a species within the Flavivirus genus of the Flaviviridae family. This family of small enveloped viruses with positive-sense RNA genomes encompasses other human pathogens, including West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and hepatitis C virus (HCV). A recent evidence-based study suggests that approximately 300 million DENV infections occur annually (1), and no vaccine or specific antiviral drug is currently available to treat it. DENV vaccine development is a major challenge due to the antibody-dependent enhancement of infection, a phenomenon in which neutralizing antibodies against one DENV serotype can exacerbate disease upon subsequent infection with another serotype (2, 3). A parallel exploration of antiviral strategies to combat DENV infection is therefore crucial.Resistance to antiviral drugs that act against viral targets occurs rapidly due to the intrinsically high mutation rate of RNA virus polymerases. Host-targeted antivirals that can complement these more traditional antivirals may make the acquisition of resistance to antiviral drugs much less likely and may also offer broad-spectrum activity against phylogenetically related viruses. The interactions between DENV and host lipid biosynthetic, metabolic, trafficking, and signal transducing pathways represent a rich and largely unexplored class of targets for host-targeted antiviral strategies. DENV and other RNA viruses rely entirely on host lipids to supply the membranes essential for the viral replication cycle, and the interaction of viruses with lipid-related processes in the host cell is highlighted by recent studies documenting specific perturbations of these pathways by viruses (4). In addition, so-called bioactive lipids can regulate cellular processes by modulating signal transduction cascades that may impinge on viral infection. Thus, small molecules that act on host-cell lipid signaling and metabolism are attractive as potential anti-DENV compounds.To pursue the strategy of targeting host lipid metabolic and signaling pathways important for DENV infection, we screened a panel of bioactive lipids and small-molecule inhibitors of lipid metabolism for activity against DENV. We chose a library enriched for compounds with known safety and bioavailability profiles to increase our likelihood of identifying clinically useful anti-DENV compounds. We present here the identification of the bioactive lipid 4-hydroxyphenyl retinamide (4-HPR) as an inhib-

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Section: Resultssupporting

confidence: 91%

The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

Carocci

Hinshaw

Rodgers

et al. 2015

Antimicrob Agents Chemother

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“…However, cholesterol is essential for most membrane processes. It was previously shown that cholesterol in cellular membranes is relevant during the first stages of flavivirus infection, suggesting that membrane cholesterol is a requirement for virus entry (33,38,63). Here we compared CSFV infectivities in cholesterol-depleted cells treated with M␤CD.…”

Section: Discussionmentioning

confidence: 99%

Entry of Classical Swine Fever Virus into PK-15 Cells via a pH-, Dynamin-, and Cholesterol-Dependent, Clathrin-Mediated Endocytic Pathway That Requires Rab5 and Rab7

Shi

Liu

Zhou

et al. 2016

J Virol

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Classical swine fever virus (CSFV), a member of the genus Pestivirus within the family Flaviviridae, is a small, enveloped, positive-strand RNA virus. Due to its economic importance to the pig industry, the biology and pathogenesis of CSFV have been investigated extensively. However, the mechanisms of CSFV entry into cells are not well characterized. In this study, we used systematic approaches to dissect CSFV cell entry. We first observed that CSFV infection was inhibited by chloroquine and NH 4 Cl, suggesting that viral entry required a low-pH environment. By using the specific inhibitor dynasore, or by expressing the dominant negative (DN) K44A mutant, we verified that dynamin is required for CSFV entry. CSFV particles were observed to colocalize with clathrin at 5 min postinternalization, and CSFV infection was significantly reduced by chlorpromazine treatment, overexpression of a dominant negative form of the EPS15 protein, or knockdown of the clathrin heavy chain by RNA interference. These results suggested that CSFV entry depends on clathrin. Additionally, we found that endocytosis of CSFV was dependent on membrane cholesterol, while neither the overexpression of a dominant negative caveolin mutant nor the knockdown of caveolin had an effect. These results further suggested that CSFV entry required cholesterol and not caveolae. Importantly, the effect of DN mutants of three Rab proteins that regulate endosomal traffic on CSFV infection was examined. Expression of DN Rab5 and Rab7 mutants, but not the DN Rab11 mutant, significantly inhibited CSFV replication. These results were confirmed by silencing of Rab5 and Rab7. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab7 during the early phase of infection within 45 min after virus entry. These results indicated that after internalization, CSFV moved to early and late endosomes before releasing its RNA. Taken together, our findings demonstrate for the first time that CSFV enters cells through the endocytic pathway, providing new insights into the life cycle of pestiviruses. IMPORTANCEBovine viral diarrhea virus (BVDV), a single-stranded, positive-sense pestivirus within the family Flaviviridae, is internalized by clathrin-dependent receptor-mediated endocytosis. However, the detailed mechanism of cell entry is unknown for other pestiviruses, such as classical swine fever (CSF) virus (CSFV). CSFV is the etiological agent of CSF, a highly contagious disease of swine that causes numerous deaths in pigs and enormous economic losses in China. Understanding the entry pathway of CSFV will not only advance our knowledge of CSFV infection and pathogenesis but also provide novel drug targets for antiviral intervention. Based on this objective, we used systematic approaches to dissect the pathway of entry of CSFV into PK-15 cells. This is the first report to show that the entry of CSFV into PK-15 cells requires a low-pH environment and involves dynamin-and cholesteroldependent, clathrin-mediated endocytosis that requires Rab5 and Rab7....

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“…For DENV, the results about the influence of cellular cholesterol on virus entry are review Castilla, Piccini & Damonte future science group controversial. The entry of DENV was found independent of plasma membrane cholesterol in C6/36, Vero, A549, HepG2, ECV304, U937, K562 and Raji-DC-SIGN cells [63][64][65]74,75,83,86], but a cholesterol dependence was observed in human monocytes and mouse neuroblastoma N18 cells [35,87]. The main strategy used in the mentioned studies to deplete or alter membrane cholesterol was the cell treatment with cholesterol-reactive drugs like methyl-β-cyclodextrin, nystatin or filipin.…”

Section: E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E mentioning

confidence: 99%

“…These agents not only affect cellular lipid membranes, but also the composition of the viral envelope. In fact, the strong virucidal activity of methyl-β cyclodextrin and nystatin against the four DENV serotypes was recently demonstrated [86]. Since the incubation of the virion suspension with the compound destroys infectivity, the cell treatment to evaluate its effect on virus entry must be done before virus infection to assess that inhibition is exerted during internalization and not by virus inactivation.…”

Section: E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E mentioning

confidence: 99%

Dengue Virus Entry and Trafficking: Perspectives as Antiviral Target for Prevention and Therapy

2015

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Dengue virus (DENV) is the etiological agent of the most important human viral infection transmitted by mosquitoes in the world. In spite of the serious health threat that dengue represents, at present there are no vaccine or antiviral agents available and treatment of patients consists of supportive therapy. This review will focus on the process of DENV entry into the host cell as a potential target for antiviral therapy. The recent advances in the knowledge of viral and cellular molecules and mechanisms involved in binding, internalization and trafficking of DENV into the host cell until virion uncoating are discussed, together with an overview of the strategies and compounds evaluated for development of antiviral agents targeted to DENV entry. KeywordsDengue is currently the most widespread arbovirosis in the world, with a particularly high prevalence in diverse tropical and subtropical regions of America and Asia [1]. The WHO estimates an occurrence of 50-100 million annual infections, but more recent modelling evaluations increased the number of new possible infections to 390 million per year [2]. There are four serotypes of dengue viruses (DENV), designated DENV-1 to DENV-4, that cocirculate and are transmitted to humans by the bites of the mosquitoes Aedes aegypti and Aedes albopictus. Precisely, the failure in the programs for control of the mosquito vector is one of the reasons for the explosive re-emergence and global spread of dengue in the last few decades in >100 countries, resulting in a serious public health challenge.All serotypes can produce either an inapparent infection or a wide spectrum of clinical outcomes ranging from a mild febrile illness known as dengue fever (DF) to the more severe and life-threatening forms of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [3]. The initial infection with one DENV serotype leads to lifelong protection against homologous reinfection, but only brief and partial protection against infection with other serotypes. In fact, the secondary infection with a heterologous serotype is considered a risk factor for developing DHF and DSS. These severe clinical manifestations have been associated to the phenomenon known as antibody-dependent enhancement (ADE) [3]. In this process, the antibodies elicited by the primary infection bind to the heterotypic virus without neutralization of viral infectivity, and these immune complexes are opsonized into Fc-receptor positive cells leading to an increase in DENV replication and pathogenesis [4,5].DENV is a member of the genus Flavivirus in the family Flaviviridae. The virion is a small spherical particle, 40-50 nm in diameter, containing a single-stranded positive sense RNA included in an inner nucleocapsid and surrounded by a lipid envelope. The virus genome codes for a single polyprotein that is cleaved into three structural proteins (the capsid protein C,

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Requirement of cholesterol in the viral envelope for dengue virus infection

Cited by 87 publications

References 48 publications

The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication

Entry of Classical Swine Fever Virus into PK-15 Cells via a pH-, Dynamin-, and Cholesterol-Dependent, Clathrin-Mediated Endocytic Pathway That Requires Rab5 and Rab7

Dengue Virus Entry and Trafficking: Perspectives as Antiviral Target for Prevention and Therapy

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