Infection of epithelial cells with dengue virus promotes the expression of proteins favoring the replication of certain viral strains

Martínez-Betancur, Viviana; Marín-Villa, Marcel; Martínez-Gutiérrez, Marlen

doi:10.1002/jmv.23857

Cited by 13 publications

(9 citation statements)

References 56 publications

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“…To determine whether virus-induced ER stress can be attributed to the PERK pathway – an important component of ER stress-mediated UPR 33 – we used three markers ( Figures 1b, c and 3c) of the PERK pathway: ATF4 (cyclic AMP-dependent transcription factor 4), GADD34 (growth arrest and DNA damage-inducible protein 34) and CHOP. 24 , 25 Dengue infection significantly increases ( P <0.002) ATF4 transcription (as measured by PCR) after 12 h ( Figure 1b ), implying PERK activation. GADD34 transcript is also significantly elevated ( Figure 1c ) at 12 and 24 h after infection.…”

Section: Resultsmentioning

confidence: 92%

“… 24 To ascertain the activation of ER stress, we examined expression of the chaperone protein calreticulin, a marker of global ER stress. 24 , 25 Calreticulin has been used as a positive indicator of ER stress in various cell types and model organisms. 26 , 27 , 28 , 29 , 30 , 31 , 32 10 6 MDCK (Madin Darby canine kidney cell line) cells were infected with dengue virus (multiplicity of infection (MOI)=5) for 24 h and were then lysed for protein extraction and western blotting.…”

Section: Resultsmentioning

confidence: 99%

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Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation

et al. 2016

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A virus that reproduces in a host without killing cells can easily establish a successful infection. Previously, we showed that dengue-2, a virus that threatens 40% of the world, induces autophagy, enabling dengue to reproduce in cells without triggering cell death. Autophagy further protects the virus-laden cells from further insults. In this study, we evaluate how it does so; we show that dengue upregulates host pathways that increase autophagy, namely endoplasmic reticulum (ER) stress and ataxia telangiectasia mutated (ATM) signaling followed by production of reactive oxygen species (ROS). Inhibition of ER stress or ATM signaling abrogates the dengue-conferred protection against other cell stressors. Direct inhibition of ER stress response in infected cells decreases autophagosome turnover, reduces ROS production and limits reproduction of dengue virus. Blocking ATM activation, which is an early response to infection, decreases transcription of ER stress response proteins, but ATM has limited impact on production of ROS and virus titers. Production of ROS determines only late-onset autophagy in infected cells and is not necessary for dengue-induced protection from stressors. Collectively, these results demonstrate that among the multiple autophagy-inducing pathways during infection, ER stress signaling is more important to viral replication and protection of cells than either ATM or ROS-mediated signaling. To limit virus production and survival of dengue-infected cells, one must address the earliest phase of autophagy, induced by ER stress.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation

et al. 2016

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“…The cells and the virus strain were maintained according to the protocols described previously [38] . Briefly, the VERO cells were maintained in Dulbecco’s Modified Eagle’s medium (DMEM; Gibco®) supplemented with 2% fetal calf serum (FCS, Gibco®) and were incubated at 37 °C in a 5% CO 2 atm.…”

Section: Methodsmentioning

confidence: 99%

In vitro and in silico anti-dengue activity of compounds obtained from Psidium guajava through bioprospecting

Trujillo-Correa

Quintero-Gil

Díaz-Castillo

et al. 2019

BMC Complement Altern Med

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BackgroundFor decades, bioprospecting has proven to be useful for the identification of compounds with pharmacological potential. Considering the great diversity of Colombian plants and the serious worldwide public health problem of dengue—a disease caused by the dengue virus (DENV)—in the present study, we evaluated the anti-DENV effects of 12 ethanolic extracts derived from plants collected in the Colombian Caribbean coast, and 5 fractions and 5 compounds derived from Psidium guajava.MethodsThe cytotoxicity and antiviral effect of 12 ethanolic extracts derived from plants collected in the Colombian Caribbean coast was evaluated in epithelial VERO cells. Five fractions were obtained by open column chromatography from the ethanolic extract with the highest selectivity index (SI) (derived from P. guajava, SI: 128.2). From the fraction with the highest selectivity (Pg-YP-I-22C, SI: 35.5), five compounds were identified by one- and two-dimensional nuclear magnetic resonance spectroscopy. The antiviral effect in vitro of the fractions and compounds was evaluated by different experimental strategies (Pre- and post-treatment) using non-toxic concentrations calculated by MTT method. The DENV inhibition was evaluated by plate focus assay. The results were analyzed by means of statistical analysis using Student’s t-test. Finally the antiviral effect in Silico was evaluated by molecular docking.ResultsIn vitro evaluation of these compounds showed that three of them (gallic acid, quercetin, and catechin) were promising antivirals as they inhibit the production of infectious viral particles via different experimental strategies, with the best antiviral being catechin (100% inhibition with a pre-treatment strategy and 91.8% with a post-treatment strategy). When testing the interactions of these compounds with the viral envelope protein in silico by docking, only naringin and hesperidin had better scores than the theoretical threshold of − 7.0 kcal/mol (− 8.0 kcal/mol and − 8.2 kcal/mol, respectively). All ligands tested except gallic acid showed higher affinity to the NS5 protein than the theoretical threshold.ConclusionEven though bioprospecting has recently been replaced by more targeted tools for identifying compounds with pharmacological potential, our results show it is still useful for this purpose. Additionally, combining in vitro and in silico evaluations allowed us to identify promising antivirals as well as their possible mechanisms of action.

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“…In the CHIKV/Col model, both compounds inhibited the production of viral particles ( Figure 6 A); for TDB-2M-ME, this inhibition would be dependent on the replication ( Figure 6 B), and, unlike that found in VERO cells, for both compounds, the inhibition would be associated with the viral protein ( Figure 6 C), because in the pre-and post-treatment strategies there was no decrease in infection ( Figure 6 D–E). These variations in activity could be related in the first place, to protein reprogramming and signaling pathways induced in the viral infection that may be dependent on the cell line [ 33 , 43 , 44 ]; and second to the cellular metabolome, which changes depending on the arboviral infection, as each type of virus produces different metabolites [ 45 ], leading to differences in the metabolisms of the compounds in each cell type.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Silico Anti-Arboviral Activities of Dihalogenated Phenolic Derivates of L-Tyrosine

et al. 2021

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Despite the serious public health problem represented by the diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses, there are still no specific licensed antivirals available for their treatment. Here, we examined the potential anti-arbovirus activity of ten di-halogenated compounds derived from L-tyrosine with modifications in amine and carboxyl groups. The activity of compounds on VERO cell line infection and the possible mechanism of action of the most promising compounds were evaluated. Finally, molecular docking between the compounds and viral and cellular proteins was evaluated in silico with Autodock Vina®, and the molecular dynamic with Gromacs®. Only two compounds (TDC-2M-ME and TDB-2M-ME) inhibited both ZIKV and CHIKV. Within the possible mechanism, in CHIKV, the two compounds decreased the number of genome copies and in the pre-treatment strategy the infectious viral particles. In the ZIKV model, only TDB-2M-ME inhibited the viral protein and demonstrate a virucidal effect. Moreover, in the U937 cell line infected with CHIKV, both compounds inhibited the viral protein and TDB-2M-ME inhibited the viral genome too. Finally, the in silico results showed a favorable binding energy between the compounds and the helicases of both viral models, the NSP3 of CHIKV and cellular proteins DDC and β2 adrenoreceptor.

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Infection of epithelial cells with dengue virus promotes the expression of proteins favoring the replication of certain viral strains

Cited by 13 publications

References 56 publications

Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation

Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation

In vitro and in silico anti-dengue activity of compounds obtained from Psidium guajava through bioprospecting

In Vitro and In Silico Anti-Arboviral Activities of Dihalogenated Phenolic Derivates of L-Tyrosine

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