Explaining Pathogenicity of Congenital Zika and Guillain–Barré Syndromes: Does Dysregulation of RNA Editing Play a Role?

Piontkivska, Helen; Miyamoto, Michael M.; Wayne, Marta L.

doi:10.1002/bies.201800239

Cited by 14 publications

(19 citation statements)

References 136 publications

(156 reference statements)

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“…In Latin America and the Caribbean, GBS incidence was estimated to have increased 2.6 times during the ZIKV outbreak [56]. It was hypothesized that ZIKV-GBS may be due to dysregulation of the activity of the RNA editing enzymes [57].…”

Section: Guillain-barré Syndrome and Emerging Infectious Diseasesmentioning

confidence: 99%

Epidemics and outbreaks of peripheral nervous system disorders: I. infectious and immune-mediated causes

et al. 2020

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Section: Guillain-barré Syndrome and Emerging Infectious Diseasesmentioning

confidence: 99%

Epidemics and outbreaks of peripheral nervous system disorders: I. infectious and immune-mediated causes

et al. 2020

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“…In the CNS, dysregulation of IRE1 signaling is implicated in a number of neurodegenerative disorders [41]. It has been suggested that neuroinflammation following infection with neurotropic viruses may play a role in these mechanisms [42][43][44][45][46]. Our observation that IRE1 activation in astrocytoma cells was stronger for the neurotropic pathogenic TBEV strain Neudoerfl, suggests that immune-mediated pathomechanisms may contribute to the severe form of the disease that is not observed for the other two viruses.…”

Section: Discussionmentioning

confidence: 69%

IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner

Breitkopf

Dobler

Claus³

et al. 2021

Viruses

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Tick-borne flaviviruses (TBFV) can cause severe neurological complications in humans, but differences in tissue tropism and pathogenicity have been described for individual virus strains. Viral protein synthesis leads to the induction of the unfolded protein response (UPR) within infected cells. The IRE1 pathway has been hypothesized to support flavivirus replication by increasing protein and lipid biogenesis. Here, we investigated the role of the UPR in TBFV infection in human astrocytes, neuronal and intestinal cell lines that had been infected with tick-borne encephalitis virus (TBEV) strains Neudoerfl and MucAr-HB-171/11 as well as Langat virus (LGTV). Both TBEV strains replicated better than LGTV in central nervous system (CNS) cells. TBEV strain MucAr-HB-171/11, which is associated with gastrointestinal symptoms, replicated best in intestinal cells. All three viruses activated the inositol-requiring enzyme 1 (IRE1) pathway via the X-box binding protein 1 (XBP1). Interestingly, the neurotropic TBEV strain Neudoerfl induced a strong upregulation of XBP1 in all cell types, but with faster kinetics in CNS cells. In contrast, TBEV strain MucAr-HB-171/11 failed to activate the IRE1 pathway in astrocytes. The low pathogenic LGTV led to a mild induction of IRE1 signaling in astrocytes and intestinal cells. When cells were treated with IRE1 inhibitors prior to infection, TBFV replication in astrocytes was significantly reduced. This confirms a supporting role of the IRE1 pathway for TBFV infection in relevant viral target cells and suggests a correlation between viral tissue tropism and the cell-type dependent induction of the unfolded protein response.

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“…5 b). Because ADARB1 and ADAR both share some overlapping editing targets as well as have gene-specific ones [ 52 , 53 ], this expression pattern suggests that both ADAR genes may play complementary roles in the differential response to ZIKV infection [ 54 ]. This would be consistent with prior suggestions that ADARB1 contributes to dysregulation of RNA editing in many diseases [ 55 – 58 ].…”

Section: Resultsmentioning

confidence: 99%

Automated Isoform Diversity Detector (AIDD): a pipeline for investigating transcriptome diversity of RNA-seq data

et al. 2020

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Background As the number of RNA-seq datasets that become available to explore transcriptome diversity increases, so does the need for easy-to-use comprehensive computational workflows. Many available tools facilitate analyses of one of the two major mechanisms of transcriptome diversity, namely, differential expression of isoforms due to alternative splicing, while the second major mechanism—RNA editing due to post-transcriptional changes of individual nucleotides—remains under-appreciated. Both these mechanisms play an essential role in physiological and diseases processes, including cancer and neurological disorders. However, elucidation of RNA editing events at transcriptome-wide level requires increasingly complex computational tools, in turn resulting in a steep entrance barrier for labs who are interested in high-throughput variant calling applications on a large scale but lack the manpower and/or computational expertise. Results Here we present an easy-to-use, fully automated, computational pipeline (Automated Isoform Diversity Detector, AIDD) that contains open source tools for various tasks needed to map transcriptome diversity, including RNA editing events. To facilitate reproducibility and avoid system dependencies, the pipeline is contained within a pre-configured VirtualBox environment. The analytical tasks and format conversions are accomplished via a set of automated scripts that enable the user to go from a set of raw data, such as fastq files, to publication-ready results and figures in one step. A publicly available dataset of Zika virus-infected neural progenitor cells is used to illustrate AIDD’s capabilities. Conclusions AIDD pipeline offers a user-friendly interface for comprehensive and reproducible RNA-seq analyses. Among unique features of AIDD are its ability to infer RNA editing patterns, including ADAR editing, and inclusion of Guttman scale patterns for time series analysis of such editing landscapes. AIDD-based results show importance of diversity of ADAR isoforms, key RNA editing enzymes linked with the innate immune system and viral infections. These findings offer insights into the potential role of ADAR editing dysregulation in the disease mechanisms, including those of congenital Zika syndrome. Because of its automated all-inclusive features, AIDD pipeline enables even a novice user to easily explore common mechanisms of transcriptome diversity, including RNA editing landscapes.

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Explaining Pathogenicity of Congenital Zika and Guillain–Barré Syndromes: Does Dysregulation of RNA Editing Play a Role?

Cited by 14 publications

References 136 publications

Epidemics and outbreaks of peripheral nervous system disorders: I. infectious and immune-mediated causes

Epidemics and outbreaks of peripheral nervous system disorders: I. infectious and immune-mediated causes

IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner

Automated Isoform Diversity Detector (AIDD): a pipeline for investigating transcriptome diversity of RNA-seq data

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