SARS-CoV-2 produces a diverse small viral RNA landscape capable of targeting host transcripts

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease (COVID-19) in humans, which may be lethal. In this study, we used a comparative transcriptomics approach to investigate the effects of SARS-CoV-2 infection on the host mRNA and sRNA expression programs in two primate cell lines. Upon infection, we observed global changes in host gene expression and differential expression of dozens of host miRNAs, many with known links to viral infection and immune response. Unexpectedly, we also discovered an expanded landscape of more than a hundred SARS-CoV-2-derived small viral RNAs (svRNAs), predicted to interact with differentially expressed host mRNAs and miRNAs. svRNAs are derived from distinct regions of the viral genome and sequence signatures suggest they are produced by a non-canonical biogenesis pathway. Our data suggest that svRNAs may play a role in SARS-CoV-2 propagation and antagonization of these svRNAs has potential for use as a therapeutic target. For Calu-3 cell experiment: 30 total samples, 5 time points, 3 SARS-CoV-2-infected and 3 control human lung epithelial cell replicates per time point. For Vero-E6 cell experiment: 21 total samples, 7 time points, 1-2 SARS-CoV-2 infected and 1 control African green monkey kidney cell replicates per time point.