Unintended consequences of innate immune activation by coronaviruses

Plonski, Noel‐Marie; Nitirahardjo, Caroline; Meindl, Richard; Piontkivska, Helen

BACKGROUND: SARS‐CoV‐2, a ssRNA virus in the same coronavirus family as SARS‐CoV‐1, is responsible for causing COVID‐19, a respiratory disorder with symptoms ranging from mild flu‐like symptoms to severe respiratory distress and organ failure. There is evidence of increased expression of inflammatory cytokines and other interferon stimulated genes (ISGs) due to innate immune activation. These have been linked with severity of symptoms and clinical outcomes of infected patients. However, there is still little known about the expression of one particular ISG, adenosine deaminase acting on RNA (ADAR), more specifically ADAR1p150 isoform that in addition to its role in transcriptome diversity is also responsible for fighting off viral infections by editing viral RNA. Genomes of both SARS‐CoV‐1 and SARS‐CoV‐2 have been shown to experience RNA editing that in turn influences viral evolution. However, the effects of altered ADAR editing patterns in the host transcriptome in coronavirus infections have not been explored. We hypothesize that changes to ADAR editing patterns, driven by differential expression of ADAR during viral infection, negatively affect protein structure and function. Changes in ADAR editing profiles can help explain underlying molecular mechanisms of the broad spectrum of symptoms seen in patients with COVID‐19. METHODS: Here we use a publicly available RNA sequencing dataset with intestinal (Caco2), lung epithelial (Calu3) and lymph node (H1299) cell lines infected with SARS‐CoV‐1 and SARS‐CoV‐2 to map differential ADAR editing patterns during infection. We used our previously developed RNA‐seq pipeline AIDD (Automated Isoform Diversity Detector) to explore immune gene expression profiles and map ADAR editing landscapes using machine learning, including Guttman scaling and random forest analysis. RESULTS: There is significantly higher expression of ADAR1p150 isoform in lung epithelial cell line, but not in the intestinal cell line or the lymph node cell line in SARS‐CoV‐2 infection. Additionally, expression of ADAR1p150 is highly correlated with identification of ADAR editing sites with high and moderate impact on protein structure and function in SARS‐CoV‐1 in lung epithelium, but is negatively correlated in intestinal cells. SARS‐CoV‐2‐infected cells show similar patterns; however, the strength of the correlation is moderate. These results indicate differential ADAR editing in protein coding regions seen in SARS‐CoV‐1 and ‐2 infections may play a role in molecular mechanisms underlying clinical symptoms seen during infection. CONCLUSIONS: Dynamic changes to protein structure and function like those caused by ADAR editing can help shed light on the pathogenesis of COVID‐19 and may provide novel investigative avenues for therapeutic options.