The Translational Landscape of SARS-CoV-2-infected Cells Reveals Suppression of Innate Immune Genes

TLDR

SARS‑CoV‑2 employs multiple strategies to modulate viral and host mRNA translation. We used ribosome profiling on infected cell lines and primary airway cells to map translational changes during infection. The virus’s mRNAs dominate the cellular pool but are not more efficiently translated, yet ribosomal frameshifting is highly efficient; infection induces transcription of chemokine, cytokine, and interferon‑stimulated genes, many of which are poorly translated, while primary cells show a subtler translational response with enhanced innate immunity and reduced ciliated cell function. These results underscore the central role of mRNA translation in SARS‑CoV‑2 replication and reveal novel therapeutic avenues.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes a number of strategies to modulate viral and host mRNA translation. Here, we used ribosome profiling in SARS-CoV-2-infected model cell lines and primary airway cells grown at an air-liquid interface to gain a deeper understanding of the translationally regulated events in response to virus replication. We found that SARS-CoV-2 mRNAs dominate the cellular mRNA pool but are not more efficiently translated than cellular mRNAs. SARS-CoV-2 utilized a highly efficient ribosomal frameshifting strategy despite notable accumulation of ribosomes within the slippery sequence on the frameshifting element. In a highly permissive cell line model, although SARS-CoV-2 infection induced the transcriptional upregulation of numerous chemokine, cytokine, and interferon-stimulated genes, many of these mRNAs were not translated efficiently. The impact of SARS-CoV-2 on host mRNA translation was more subtle in primary cells, with marked transcriptional and translational upregulation of inflammatory and innate immune responses and downregulation of processes involved in ciliated cell function. Together, these data reveal the key role of mRNA translation in SARS-CoV-2 replication and highlight unique mechanisms for therapeutic development.