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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\n                    <jats:italic>Betacoronavirus<\/jats:italic>\n                    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-CoV-2 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\u03b1 and ATF6 branches of the UPR were inhibited, reducing SARS-CoV-2 virion release (~1,000-fold). Together, these data highlight the UPR as a promising antiviral target to combat coronavirus infection.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009644","type":"journal-article","created":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T13:26:12Z","timestamp":1623936372000},"page":"e1009644","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":96,"title":["Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9024-3860","authenticated-orcid":true,"given":"Liliana","family":"Echavarr\u00eda-Consuegra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1577-735X","authenticated-orcid":true,"given":"Georgia 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