Differential RNA editing landscapes in host cell versus the SARS-CoV-2 genome

The ongoing SARS-CoV-2 pandemic has been impressed by the emergence of new viral variants formed through virus mutation that may originate from: (i) random errors not corrected by the built-in proofreading system and (ii) host antiviral response introducing mutations into the viral genome (including ADARs and/or APOBECs, and reactive oxygen species mediated RNA editing). We investigated the transcriptome of cells infected with two strains of SARS-CoV-2 representing the original European (B.1, D614G) and alpha (B.1.1.7) lineages. We studied the frequency and type of mutations within the viral RNA genome during single-round infection and serial passaging by direct sequencing. The two variants showed both different cellular responses and mutation patterns. Alpha exhibits more substitutions in the RNA genome than EDB-2, with the most frequent substitution observed in alpha being C-U. As a control, the most predominant RNA editing in host RNA was A-G, indicating that global viral and host RNA editing signatures are distinct. Whilst knockdown of APOBEC1 and select APOBEC3s through RNAi increased virus production in original, no such effect was seen for alpha, delta, and omicron variants. Overall, this suggests a deaminase-independent antiviral function of APOBECs in SARS-CoV-2 whilst the editing function may be beneficial to enhance genetic diversity.