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Full text of this paper is not available in the ETD Center. Copies may be available for inter-library loan from Kent State University or may be available for purchase from Proquest/UMI

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The role of RNA-editing in viral mediated pathogenesis

Frederick , Madeline Rose
http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors152545654349718

Abstract Details

2018, BA, Kent State University, College of Arts and Sciences / Department of Biological Sciences.
Zika Virus (ZIKV) is a flavivirus that in 2016 was designated as an international public health emergency by WHO due to its link with neurodevelopmental defects in infants including microcephaly. These birth defects are now referred to as the congenital Zika syndrome (CZS). Our recent findings showed that ZIKV genomes harbor footprints of ADAR editing (Piontkivska, Frederick, et al. 2017), an important player in both post-transcriptional regulation and innate immune response. Because of prominent role of ADAR editing in brain development, ADARs can potentially play a causative role in neurodevelopmental defects of CZS, although their exact role and contribution remain to be delineated. The Dengue Virus (DENV), another pathogenic flavivirus, has been associated with major infections worldwide, including Dengue Hemorrhagic Fever and Dengue Shock Syndrome, but has not been linked to congenital symptoms. We hypothesize that this difference can be attributed to distinct mechanisms of pathogenicity, where ZIKV as a mild infection generates a stronger innate rather than adaptive immune response, with a major role being played by the cell-autonomous immunity, whereas DENV triggers a stronger adaptive rather than innate immune response. By primarily provoking the innate immune response, ZIKV is activating interferon (IFN) type 1 pathways, causing a gene-activation cascade that ultimately activates Adenosine Deaminases acting on RNA (ADARs). Thus, we can expect that when ADARs are dysregulated by ZIKV infection, this results in changes of transcript editing. These changes in turn lead to the amino acid changes in now (mis)edited proteins that may be responsible for a cascade of cytopathic effects in the brain, ultimately resulting in neurodevelopmental defects. To test the central premise of this hypothesized cascade, we used a bioinformatics pipeline developed in our lab, the AIDD, and publically available RNAseq data, to compare whether the innate and adaptive immunity genes are expressed differently between ZIKV- and DENV-infected cells, with particular focus on ADAR genes. Gene enrichment and pathway analysis were performed using DAVID and PANTHER. Our results indicate that in agreement with our expectations, DENV-infected cells show upregulation of genes involved in the adaptive immune response. On the other hand, ZIKV-infected cells show activation of innate immunity related genes. Further, ZIKV-infected cells with the most severe cytopathic effects also exhibit an increase in ADAR1 gene expression, supporting the hypothesis that the IFN type 1 pathway plays a significant role in ZIKV infection. Lack of ADAR1 upregulation in ZIKV-infected cell line without clear cytopathic effects is consistent with our central hypothesis that activation of ADAR expression, and thus expected downstream editing changes of neural target transcripts, may play a role in phenotypic changes in CZS.
Helen Piontkivska (Advisor)
Noel-Marie Plonski (Other)
Bioinformatics; Biology

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Citations

  • Frederick , M. R. (2018). The role of RNA-editing in viral mediated pathogenesis [Undergraduate thesis, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors152545654349718

    APA Style (7th edition)

  • Frederick , Madeline . The role of RNA-editing in viral mediated pathogenesis. 2018. Kent State University, Undergraduate thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors152545654349718.

    MLA Style (8th edition)

  • Frederick , Madeline . "The role of RNA-editing in viral mediated pathogenesis." Undergraduate thesis, Kent State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors152545654349718

    Chicago Manual of Style (17th edition)

ksuhonors152545654349718