Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?

Turpin, Jonathan; Safadi, Daed El; Lebeau, Grégorie; Krejbich, Morgane; Chatelain, Camille; Desprès, Philippe; Viranaïcken, Wildriss; Krejbich-Trotot, Pascale

doi:10.3390/ijms23031287

Cited by 16 publications

(10 citation statements)

References 164 publications

(219 reference statements)

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“…Moreover, the cytoprotection effects observed for LabMol-297, LabMol-201, LabMol-212, LabMol-298, LabMol-194, LabMol-300, LabMol-301, and LabMol-305 could be related to the blockage of human apoptotic pathways that ZIKV commonly induces, such as caspase-3-mediated pathways; pro-apoptotic B-cell lymphoma protein 2 (Bcl-2)-mediated family pathways through NS proteins; C/EBP homologous protein (CHOP); double-stranded RNA and toll-like receptor (DsRNA/TLR3) through NS2B-NS3pro; or fibroblast growth factor 2 (FGF2) . We can hypothesize that our compounds could act by inhibiting caspase-3, which would agree with our GSC387 cell assays.…”

Section: Resultsmentioning

confidence: 99%

Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika

Mottin

Sousa

Mesquita

et al. 2022

J. Chem. Inf. Model.

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The Zika virus (ZIKV) is a neurotropic arbovirus considered a global threat to public health. Although there have been several efforts in drug discovery projects for ZIKV in recent years, there are still no antiviral drugs approved to date. Here, we describe the results of a global collaborative crowdsourced open science project, the OpenZika project, from IBM's World Community Grid (WCG), which integrates different computational and experimental strategies for advancing a drug candidate for ZIKV. Initially, molecular docking protocols were developed to identify potential inhibitors of ZIKV NS5 RNA-dependent RNA polymerase (NS5 RdRp), NS3 protease (NS2B-NS3pro), and NS3 helicase (NS3hel). Then, a machine learning (ML) model was built to distinguish active vs inactive compounds for the cytoprotective effect against ZIKV infection. We performed three independent target-based virtual screening campaigns (NS5 RdRp, NS2B-NS3pro, and NS3hel), followed by predictions by the ML model and other filters, and prioritized a total of 61 compounds for further testing in enzymatic and phenotypic assays. This yielded five non-nucleoside compounds which showed inhibitory activity against ZIKV NS5 RdRp in enzymatic assays (IC 50 range from 0.61 to 17 μM). Two compounds thermally destabilized NS3hel and showed binding affinity in the micromolar range (K d range from 9 to 35 μM). Moreover, the compounds LabMol-301 inhibited both NS5 RdRp and NS2B-NS3pro (IC 50 of 0.8 and 7.4 μM, respectively) and LabMol-212 thermally destabilized the ZIKV NS3hel (K d of 35 μM). Both also protected cells from death induced by ZIKV infection in in vitro cell-based assays. However, while eight compounds (including LabMol-301 and LabMol-212) showed a cytoprotective effect and prevented ZIKV-induced cell death, agreeing with our ML model for prediction of this cytoprotective effect, no compound showed a direct antiviral effect against ZIKV. Thus, the new scaffolds discovered here are promising hits for future structural optimization and for advancing the discovery of further drug candidates for ZIKV. Furthermore, this work has demonstrated the importance of the integration of computational and experimental approaches, as well as the potential of large-scale collaborative networks to advance drug discovery projects for neglected diseases and emerging viruses, despite the lack of available direct antiviral activity and cytoprotective effect data, that reflects on the assertiveness of the computational predictions. The importance of these efforts rests with the need to be prepared for future viral epidemic and pandemic outbreaks.

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Section: Resultsmentioning

confidence: 99%

Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika

Mottin

Sousa

Mesquita

et al. 2022

J. Chem. Inf. Model.

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“…Flow cytometry analysis showed that B cells in the spleen and bone marrow were infected with ZIKV, suggesting B cell levels may be reduced due to either apoptosis or arrested maturation or both. While ZIKV induced apoptosis was evaluated in vitro in various contexts ( 74 ), data has been lacking on the effect of the virus on fetal immune cell development in vivo . Lymphopoiesis begins at 6 weeks post-conception in the fetal liver ( 75 ).…”

Section: Discussionmentioning

confidence: 99%

Zika virus induced microcephaly and aberrant hematopoietic cell differentiation modeled in novel neonatal humanized mice

et al. 2023

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IntroductionImmunocompetent and immunocompromised murine models have been instrumental in answering important questions regarding ZIKV pathogenesis and vertical transmission. However, mimicking human congenital zika syndrome (CZS) characteristics in these murine models has been less than optimal and does not address the potential viral effects on the human immune system.MethodsHere, we utilized neonatal humanized Rag2-/-γc-/- mice to model CZS and evaluate the potential viral effects on the differentiation of human hematopoietic stem cells in vivo. Newborn Rag2-/-γc-/- mice were engrafted with ZIKV-infected hematopoietic stem cells (HSC) and monitored for symptoms and lesions.ResultsWithin 13 days, mice displayed outward clinical symptoms that encompassed stunted growth, hunched posture, ruffled fur, and ocular defects. Striking gross pathologies in the brain and visceral organs were noted. Our results also confirmed that ZIKV actively infected human CD34+ hematopoietic stem cells and restricted the development of terminally differentiated B cells. Histologically, there was multifocal mineralization in several different regions of the brain together with ZIKV antigen co-localization. Diffuse necrosis of pyramidal neurons was seen with collapse of the hippocampal formation.DiscussionOverall, this model recapitulated ZIKV microcephaly and CZS together with viral adverse effects on the human immune cell ontogeny thus providing a unique in vivo model to assess the efficacy of novel therapeutics and immune interventions.

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“…But ZIKV could also impair the expression of CHOP and delay the ER-stress driven apoptosis [ 41 ]. Depending on its early or delayed occurrence, ZIKV-induced apoptosis could impose a duality of the effect in viral pathogenesis [ 42 ]. Pro-apoptotic factors in ZIKV-infected neuroprogenitor cells lead to induce early apoptosis, which may contribute to congenital defects in the brain of newborns.…”

Section: Discussionmentioning

confidence: 99%

“…Other factors including upregulation of anti-apoptotic Bcl-2 or inhibition of the CHOP function can delay apoptosis in the reproductive or genital tract. Thus the delayed apoptosis may benefit ZIKV persistent infection for sexual transmission [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Concomitant pyroptotic and apoptotic cell death triggered in macrophages infected by Zika virus

Wen

Gao

et al. 2022

PLoS ONE

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Zika virus (ZIKV) is a positive-sense RNA flavivirus and can cause serious neurological disorders including microcephaly in infected fetuses. As a mosquito-borne arbovirus, it enters the bloodstream and replicates in various organs. During pregnancy, it can be transmitted from the blood of the viremic mother to the fetus by crossing the placental barrier. Monocytes and macrophages are considered the earliest blood cell types to be infected by ZIKV. As a first line defense, these cells are crucial components in innate immunity and host responses and may impact viral pathogenesis in humans. Previous studies have shown that ZIKV infection can activate inflammasomes and induce proinflammatory cytokines in monocytes. In this report, we showed that ZIKV could infect and induce cell death in human and murine macrophages. In addition to the presence of cleaved caspase-3, indicating that apoptosis was involved, we identified the cleaved caspase-1 and gasdermin D (GSDMD) as well as increased secretion of IL-1β and IL-18. This suggests that the inflammasome was activated and that may lead to pyroptosis in infected macrophages. The pyroptosis was NLRP3-dependent and could be suppressed in the macrophages treated with shRNA to target and knockdown caspase-1. It was also be inhibited by an inhibitor for caspase-1, indicating that the pyroptosis was triggered via a canonical approach. Our findings in this study demonstrate a concomitant occurrence of apoptosis and pyroptosis in ZIKV-infected macrophages, with two mechanisms involved in the cell death, which may have potentially significant impacts on viral pathogenesis in humans.

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Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?

Cited by 16 publications

References 164 publications

Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika

Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika

Zika virus induced microcephaly and aberrant hematopoietic cell differentiation modeled in novel neonatal humanized mice

Concomitant pyroptotic and apoptotic cell death triggered in macrophages infected by Zika virus

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