Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection

Coronavirus infection induces the unfolded protein response (UPR), a cellular signalling pathway composed of three branches, triggered by unfolded proteins in the endoplasmic reticulum (ER) due to high ER load. We have used RNA sequencing and ribosome profiling to investigate holistically the transcriptional and translational response to cellular infection by murine hepatitis virus (MHV), often used as a model for the Betacoronavirus genus to which the recently emerged SARS-CoV-2 also belongs. We found the UPR to be amongst the most significantly up-regulated pathways in response to MHV infection. To confirm and extend these observations, we show experimentally the induction of all three branches of the UPR in both MHV- and SARS-CoV-2-infected cells. Over-expression of the SARS-CoV2 ORF8 or S proteins alone is itself sufficient to induce the UPR. Remarkably, pharmacological inhibition of the UPR greatly reduced the replication of both MHV and SARS-CoV-2, revealing the importance of this pathway for successful coronavirus replication. This was particularly striking when both IRE1 alpha and ATF6 branches of the UPR were inhibited, reducing SARS-CoV-2 virion release (similar to 1,000-fold). Together, these data highlight the UPR as a promising antiviral target to combat coronavirus infection.

Automated summary

Coronavirus infection triggers the unfolded protein response (UPR) in cells, and inhibiting UPR with drugs can significantly reduce virus replication. This study suggests that UPR may be a promising antiviral target in combating coronavirus infections.