Betacoronavirus-specific alternate splicing

Viruses can subvert a number of cellular processes including splicing in order to block innate antiviral responses, and many viruses interact with cellular splicing machinery. SARS-CoV-2 infection was shown to suppress global mRNA splicing, and at least 10 SARS-CoV-2 proteins bind specifically to one or more human RNAs. Here, we investigate 17 published experimental and clinical datasets related to SARS-CoV-2 infection, datasets from the betacoronaviruses SARS-CoV and MERS, as well as Streptococcus pneumonia, HCV, Zika virus, Dengue virus, influenza H3N2, and RSV. We show that genes showing differential alternative splicing in SARS-CoV-2 have a similar functional profile to those of SARS-CoV and MERS and affect a diverse set of genes and biological functions, including many closely related to virus biology. Additionally, the differentially spliced transcripts of cells infected by coronaviruses were more likely to undergo intron-retention, contain a pseudouridine modifi-cation, and have a smaller number of exons as compared with differentially spliced transcripts in the control groups. Viral load in clinical COVID-19 samples was correlated with isoform distribution of differentially spliced genes. A significantly higher number of ribosomal genes are affected by differential alternative splicing and gene expression in betacoronavirus samples, and the betacoronavirus differentially spliced genes are depleted for binding sites of RNA-binding proteins. Our results demonstrate characteristic patterns of differential splicing in cells infected by SARS-CoV-2, SARS-CoV, and MERS. The alternative splicing changes observed in betacor-onaviruses infection potentially modify a broad range of cellular functions, via changes in the functions of the products of a diverse set of genes involved in different biological processes.

Automated summary

Viruses, including SARS-CoV-2, can manipulate cellular splicing processes to evade antiviral responses. In this study, the authors investigated the differential alternative splicing patterns in cells infected by SARS-CoV-2 and other viruses. They found that these splicing changes affect a diverse set of genes and biological functions, many of which are closely related to virus biology. The results also suggest that the isoform distribution of differentially spliced genes is correlated with viral load in clinical COVID-19 samples. Moreover, the differential splicing in betacoronaviruses infection affects a significant number of ribosomal genes and is associated with the absence of RNA-binding protein binding sites.