The landscape of differential splicing and transcript alternations in severe COVID-19 infection.

Viral infections can modulate the widespread alternations of cellular splicing, favoring viral replication within the host cells by overcoming host immune responses. However, how SARS-CoV-2 induces host cell differential splicing and affects the landscape of transcript alternation in severe COVID-19 infection remains elusive. Understanding the differential splicing and transcript alternations in severe COVID-19 infection may improve our molecular insights into the SARS-CoV-2 pathogenesis. In this study, we analyzed the publicly available blood and lung transcriptome data of severe COVID-19 patients, blood transcriptome data of recovered COVID-19 patients at 12-, 16-, and 24-weeks post-infection, and healthy controls. We identified a significant transcript isoform switching in the individual blood and lungs RNA-seq data of severe COVID-19 infected patients and 25 common genes that alter their transcript isoform in both blood and lung samples. Altered transcripts show significant loss of the open reading frame, functional domains, and switch from coding to non-coding transcript, impacting normal cellular functions. Furthermore, we identified the expression of several novel recurrent chimeric transcripts in the blood samples from severe COVID-19 patients. Moreover, analysis of the isoform switching in blood samples from recovered COVID-19 patients highlights that there is no significant isoform switching in 16 -, and 24-weeks post-infection, and the levels of expressed chimeric transcripts are reduced. This finding emphasizes that SARS-CoV-2 severe infection induces widespread splicing in the host cells, which could help the virus alter the host immune responses and facilitate the viral replication within the host and the efficient translation of viral proteins.