Cellular APOBEC3A deaminase drives mutations in the SARS-CoV-2 genome

Area of Science:

• Virology
• Molecular Biology
• Genetics

Background:

• SARS-CoV-2 genetic variation arises from continuous viral mutations.
• Understanding host factors influencing viral mutation is crucial for controlling pandemics.

Purpose of the Study:

• To investigate the role of human cytidine deaminases in SARS-CoV-2 genome mutation.
• To identify host factors that contribute to SARS-CoV-2 genetic diversity.

Main Methods:

• Bioinformatic analysis of SARS-CoV-2 genomic sequences.
• Exogenous expression of APOBEC3A (A3A) in infected cells.
• Analysis of A3A mRNA expression in response to interferons (IFNs) and tumor necrosis factor-α (TNF-α).
• CRISPR/Cas9-based knockout of A3A in lung epithelial cells.

Main Results:

• A significant UC-to-UU mutation signature, characteristic of A3A activity, was identified in SARS-CoV-2 RNA.
• Exogenous A3A expression induced UC-to-UU mutations in viral RNA, particularly in single-stranded regions.
• IFNs and TNF-α significantly upregulated A3A mRNA expression in respiratory epithelial cells.
• Increased viral mutation rates were observed in cells treated with IFN-ß and TNF-α, but not in A3A-knockout cells.

Conclusions:

• Human APOBEC3A (A3A) is a key host factor responsible for C-to-U RNA editing in the SARS-CoV-2 genome.
• A3A-mediated mutations are influenced by host immune responses, specifically IFNs and TNF-α.
• Targeting A3A activity could be a potential strategy to control SARS-CoV-2 evolution and virulence.