Pathological Implications of Repression of Cellular RNA Decay by Zika Virus

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PROJECT SUMMARY / ABSTRACT Zika virus is an emerging flavivirus that presents a significant risk to pregnant women and is associated with Guillian-Barre syndrome. Why the virus elicits these unforeseen pathologies is unclear, but is undoubtedly related to unique aspects of Zika virus-host interactions – a highly understudied area of investigation to date. Previous work from our laboratory has demonstrated that RNAs from other insect-borne flaviviruses contain a highly structured segment in their 3' UTR that stalls and represses the cellular exoribonuclease Xrn1. Repression of this major cellular RNA decay enzyme causes significant dysregulation of global cellular gene expression, changes that are likely very relevant to virus-induced cytopathology and pathogenesis. The first goal of this project is to demonstrate the stalling and repression of Xrn1 by Zika virus RNAs that we hypothesize should occur based on modeling with the RNAs of other flaviviruses. Importantly, we will then analyze the implications that Xrn1 repression has on Zika virus infection of cell types that are biologically relevant to fetal tissues that are particularly sensitive to virus infection in utero. Second, we will explore the possible functions of the non-coding ~400 base RNA (sfRNA) that is generated by Xrn 1 stalling and accumulates to high levels during infection. This study will for the first time explore the roles of the Zika virus 3' non-coding RNA region in virus-host interactions. We hypothesize that the Zika sfRNA likely accumulates to high levels in infected cells and may serve as a sponge to disrupt the function and/or usurp the activity of key cellular RNA binding proteins. These data should provide foundational insights for understanding Zika virus pathogenesis as well as identify novel targets for antiviral drug development or virus attenuation for vaccine production.