Abnormal global alternative RNA splicing in COVID-19 patients

Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.

Author summary
Despite intensive studies on the transcriptional signatures of COVID-19 patients, how SARS-CoV-2 affects AS landscape and the contribution of AS to the pathogenesis of COVID-19 remain largely elusive. By profiling the lung transcriptome and lung proteome of nine patients who died of COVID-19 during the first wave of the pandemic in Wuhan, China, we obtained molecular insights into the AS of cellular transcripts upon SARS-CoV-2 infection. Interestingly, SARS-CoV-2 proteins directly engage host spliceosome to dysregulate essential steps of mature mRNA production and result in widespread dysregulation of cellular function. Taken together, our findings shed light on COVID-19 molecular mechanism and offer potential therapeutic targets for severe COVID-19 disease.