ADAR1-mediated antiviral response in Zika virus (ZIKV) infection - 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.