SARS-CoV-2-induced dysregulation in ADAR editing patterns persists post viral clearance in individuals with mild COVID-19.

Introduction: Innate immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection activates multiple interferon stimulated genes (ISGs), including ADAR1 p150 isoform, which edits adenosine (A) residues within double stranded RNAs in both the virus and the host. In addition to its immune role, ADAR editing also serves as a mechanism of dynamic regulation of transcriptome and proteome diversity. While evidence points to changes in ADAR editing during infection, we do not know whether editing targets change over the course of the infection. Methods: Here, we explored temporal changes in ADAR expression and editing patterns, across three distinct stages of SARS-CoV-2 infection. Furthermore, we examined whether infection-triggered dysregulation in ADAR editing persists or returns to pre-infection states post-viral clearance using publicly available whole blood RNA sequencing samples from forty-five, age-matched individuals. The individuals selected had no documented comorbidities, developed mild COVID-19, and were sampled across three distinct stages of SARS-CoV-2 infection: pre-, mid-, and post-infection. Results and discussion: Our results demonstrate dynamic changes in ADAR expression and editing across the three stages. We further identified editing sites that were edited only in one of the three stages of infection within genes involved in immune response pathways, specifically, within neutrophil degranulation pathway genes. Our results demonstrate a consistent trend of elevated ADAR expression and reduced overall ADAR editing within each individual mid-infection. Subsequently, post-infection, though ADAR expression returns to pre-infection levels, ADAR editing remains dysregulated in some individuals. Given that dysregulated ADAR editing could be a mechanistic link between viral infections and sequalae, it is possible that persistent dysregulation of ADAR editing in a subset of recovered individuals contributes to the heterogeneity in disease outcomes seen in individuals post-SARS-CoV-2 infection.