Wednesday, December 6, 2023
12/6/2023
Project Summary In response to viral infections, host cells trigger an innate/anti-viral immune response, predominantly by producing the interferons (IFNs) and IFN-stimulated genes (ISGs). These anti- viral responses promote inflammation, immune cell activation, and viral clearance. We recently reported that retinal pigment epithelium (RPE) and retinal vascular or choroidal endothelium are highly permissive to Zika virus (ZIKV) infection and elicit antiviral response with increased production of IFNs and ISGs. The transcriptomic analysis of ZIKV-infected RPE revealed the induction of adenosine deaminases acting on RNA1 (ADAR1), a potent ISG, which can exert pro- or antiviral activity by A-to-I editing of the host and viral RNA. The role and mechanisms of action of ADAR1 during ZIKV and related flaviviruses have not been studied till now. Our preliminary studies show that 1) ADAR1 is up-regulated at the transcript, as well as, protein levels upon ZIKV infection in RPE cells, and 2) ADAR1 overexpression reduced, while ADAR1 knockdown increased, ZIKV replication in RPE cells. These findings led us to investigate the role of ADAR1 in retinal innate immunity to ZIKV and other flaviviruses. Thus, the overall goal of this proposal is to determine the mechanisms of antiviral actions of ADAR1 in attenuating ZIKV replication in RPE cells (Aim 1); and to determine the consequences of ADAR1 ablation and ADAR1 overexpression on ZIKV-induced chorioretinal atrophy in a mouse model (Aim 2). The proposed studies will broaden and deepen our knowledge of the antiviral response during ocular ZIKV infection. Our studies could also identify new targets and treatment modalities based on the RNA editing ability of the host.
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