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

Summary

The SARS-CoV-2 pandemic was defined by the emergence of new variants formed through virus mutation originating from random errors not corrected by viral proofreading and/or the host antiviral response introducing mutations into the viral genome. While sequencing information hints at cellular RNA editing pathways playing a role in viral evolution, here, we use an in vitro human cell infection model to assess RNA mutation types in two SARS-CoV-2 strains representing the original and the alpha variants. The variants showed both different cellular responses and mutation patterns with alpha showing higher mutation frequency with most substitutions observed being C-U, indicating an important role for apolipoprotein B mRNA editing catalytic polypeptide-like editing. Knockdown of select APOBEC3s through RNAi increased virus production in the original virus, but not in alpha. Overall, these data suggest a deaminase-independent anti-viral function of APOBECs in SARS-CoV-2 while the C-U editing itself might function to enhance genetic diversity enabling evolutionary adaptation.

Graphical abstract

Highlights

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  RNA-modifying enzymes are upregulated upon SARS-CoV-2 infection in vitro

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  SARS-CoV-2 VOC Alpha shows a significant increase of C-U RNA edits

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  Knockdown of APOBEC3B and 3D increases virus replication of original SARS-CoV-2

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  Effect of APOBEC3B and 3D knockdown disappears in VOCs Alpha, Delta, and Omicron

Abstract

Virology; Evolutionary biology