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bioRxiv · 10.1101/2021.08.23.457314

Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection

Iida, K.·Ajiro, M.·Muramoto, Y.·Takenaga, T.·Denawa, M.·Kurosawa, R.·Noda, T.·Hagiwara, M.
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Abstract

BackgroundThe rapidly accumulating disease susceptibility information collected from coronavirus disease (COVID-19) patient genomes must be urgently utilized to develop therapeutic interventions for SARS-CoV-2 infection. Chromosome 12q24.13, which encodes the 2-5-oligoadenylate synthetase (OAS) family of proteins that sense viral genomic RNAs and trigger an antiviral response, is identified as one of the genomic regions that contains SNPs associated with COVID-19 severity. A high-risk SNP identified at the splice acceptor site of OAS1 exon 6 is known to change the proportions of the various splicing isoforms and the activity of the enzyme. MethodsWe employed in-silico motif search and RNA pull-down assay to define a factor responsible for the OAS1 splicing. Next, we rationally selected a candidate for slicing modulator to modulate this splicing. ResultsWe found that inhibition of CDC-like kinase with a small chemical compound induces switching of OAS1 splice isoforms in human lung cells. In this condition, increased resistance to SARS-CoV-2 infection, enhanced RNA degradation, and transcriptional activation of interferon {beta}1, were also observed. ConclusionsThe results indicate the possibility of using chemical splicing modifiers aided by genome-based precision medicine to boost the innate immune response against SARS-CoV-2 infection.

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Iida, K., Ajiro, M., Muramoto, Y., Takenaga, T., Denawa, M., Kurosawa, R., Noda, T., Hagiwara, M.. 2021-08-23. Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection. https://doi.org/10.1101/2021.08.23.457314

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