West Nile Virus Infection Induces Interferon Signalling in Human Retinal Pigment Epithelial Cells

Činátl, Jindřich; Michaelis, Martin; Fleckenstein, Corinna; Bauer, Gabriele; Kabičková, Hanka; Scholz, Martin; Rabenau, Holger F.; Doerr, Hans Wilhelm

doi:10.1167/iovs.05-1022

Cited by 25 publications

(20 citation statements)

References 34 publications

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“…The accumulation of viral proteins correlated with decreasing cell viability and the level of observed cytopathic effects. Similar observation demonstrating that the induction of cell death can happen independently of WNV-replication were made before using other cell types including human kidney cell line 293 and human retinal pigment epithelial cells [17,18]. Taken together, these data suggest that the treatment with inhibitors of virus replication at later time points p.i.…”

Section: Discussionsupporting

confidence: 84%

Inhibition of apoptosis prevents West Nile virus induced cell death

et al. 2007

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Section: Discussionsupporting

confidence: 84%

Inhibition of apoptosis prevents West Nile virus induced cell death

et al. 2007

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“…44–51 Multiple reports, describing different aspects of the virus-retinal pigment epithelial cell interaction, reveal infected cells may mount a type I IFN response 46,47,51 and an inflammatory cytokine response. 48,50,51 Of direct relevance to our findings in EBOV-infected retinal pigment epithelial cells, some of these reports further imply the epithelium has a specific molecular phenotype that might promote persistence of live virus within the eye.…”

Section: Discussionmentioning

confidence: 99%

Retinal Pigment Epithelial Cells are a Potential Reservoir for Ebola Virus in the Human Eye

Smith

Todd

Ashander

et al. 2017

Trans. Vis. Sci. Tech.

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PurposeSuccess of Ebola virus (EBOV) as a human pathogen relates at the molecular level primarily to blockade the host cell type I interferon (IFN) antiviral response. Most individuals who survive Ebola virus disease (EVD) develop a chronic disease syndrome: approximately one-quarter of survivors suffer from uveitis, which has been associated with presence of EBOV within the eye. Clinical observations of post-Ebola uveitis indicate involvement of retinal pigment epithelial cells.MethodsWe inoculated ARPE-19 human retinal pigment epithelial cells with EBOV, and followed course of infection by immunocytochemistry and measurement of titer in culture supernatant. To interrogate transcriptional responses of infected cells, we combined RNA sequencing with in silico pathway, gene ontology, transcription factor binding site, and network analyses. We measured infection-induced changes of selected transcripts by reverse transcription-quantitative polymerase chain reaction.ResultsHuman retinal pigment epithelial cells were permissive to infection with EBOV, and supported viral replication and release of virus in high titer. Unexpectedly, 28% of 560 upregulated transcripts in EBOV-infected cells were type I IFN responsive, indicating a robust type I IFN response. Following EBOV infection, cells continued to express multiple immunomodulatory molecules linked to ocular immune privilege.ConclusionsHuman retinal pigment epithelial cells may serve as an intraocular reservoir for EBOV, and the molecular response of infected cells may contribute to the persistence of live EBOV within the human eye.Translational RelevanceThis bedside-to-bench research links ophthalmic findings in survivors of EVD who suffer from uveitis with interactions between retinal pigment epithelial cells and EBOV.

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“…Total RNA was isolated from cell cultures using the TRI reagent (Sigma-Aldrich). Reverse transcription and real-time PCRs were performed as described before (15). The following primer sequences were used: 18s rRNA forward 5 ¶-GTGAAACTGCGAATGGCTCAT, 18s rRNA reverse 5 ¶-CTGACCGGGTTGGTTTTGAT, 18s rRNA probe 5 ¶-(VIC) TGGTCGCTCCTCTCCCAC-(TAMRA), MDM2 forward 5 ¶-TGTTGGTGCA-CAAAAAGACA, MDM2 reverse 5 ¶-CACGCCAAACAAATCTCCTA, p21 forward 5 ¶-GCCCGTGAGCGATGGAA, p21 reverse 5 ¶-ACGCTCCCAGGC-GAAGTC, GADD45 forward 5 ¶-GCACGCCGCGCTCTCT, GADD45 reverse CTTATCCATCCTTTCGGTCTTCTG.…”

Section: Methodsmentioning

confidence: 99%

Reversal of P-glycoprotein–Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3

et al. 2009

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Murine double minute 2 (MDM2) negatively regulates the activity of the tumor suppressor protein p53. Nutlin-3 is a MDM2 inhibitor under preclinical investigation as nongenotoxic activator of the p53 pathway for cancer therapy. Here, nutlin-3 was evaluated for its activity alone or in combination with established chemotherapeutic drugs for antitumor action in chemosensitive and chemoresistant neuroblastoma and rhabdomyosarcoma cell lines. Effects of nutlin-3 single treatment were much more pronounced in p53 wild-type cell lines (IC 50 s <3 Mmol/L) than in p53-mutated cell lines (IC 50 s >17 Mmol/L). In sharp contrast to the expectations, nutlin-3 concentrations that did not affect viability of p53-mutated cell lines strongly increased the efficacy of vincristine in p53-mutated, P-glycoprotein (P-gp)-overexpressing cell lines (decrease in IC 50 s 92-to 3,434-fold). Similar results were obtained for other P-gp substrates. Moreover, nutlin-3 reduced efflux of rhodamine 123 and other fluorescence dyes that are effluxed by P-gp. Investigation of Madin-Darby canine kidney (MDCK) II cells stably transfected with plasmids encoding for P-gp (MDCKII MDR1) or multidrug resistance protein 1 (MRP-1, MDCKII MRP1) revealed that nutlin-3 not only interferes with P-gp but also affects MRP-1-mediated efflux. Kinetic studies and investigation of P-gp-ATPase activity showed that nutlin-3 is likely to act as a P-gp transport substrate. Examination of the nutlin-3 enantiomers nutlin-3a and nutlin-3b revealed that, in contrast to MDM2-inhibitory activity that is limited to nutlin-3a, both enantiomers similarly interfere with P-gp-mediated drug efflux. In conclusion, nutlin-3-induced inhibition of P-gp and MRP-1 was discovered as a novel anticancer mechanism of the substance in this report. [Cancer Res 2009;69(2):416-21]

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West Nile Virus Infection Induces Interferon Signalling in Human Retinal Pigment Epithelial Cells

Cited by 25 publications

References 34 publications

Inhibition of apoptosis prevents West Nile virus induced cell death

Inhibition of apoptosis prevents West Nile virus induced cell death

Retinal Pigment Epithelial Cells are a Potential Reservoir for Ebola Virus in the Human Eye

Reversal of P-glycoprotein–Mediated Multidrug Resistance by the Murine Double Minute 2 Antagonist Nutlin-3

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