In contrast to RSV and IAV infection, the human CoVs demonstrate a distinct UPR profile. Three human coronaviruses (MERS-CoV, HCoV-OC43 and SARS-CoV-2) replicate efficiently in IRE1 deficient cells, suggesting IRE1 activation is not necessary for CoV replication . Extensive and prolonged induction of IRE1 in CoV infection may in fact favour a pro-apoptotic response rather than beneficial responses such as increased chaperone expression aimed at restoring homeostasis . Although SARS-CoV-2 induces IRE1, downstream XBP1 splicing is actually suppressed by the virus, perhaps to limit cytokine signalling that could trigger detection by the host immune system . SARS-CoV-1 selectively activates PERK rather than IRE1, to promote its replication. PERK-associated ER chaperones are upregulated via eIF2⍺, while CHOP, the apoptosis-associated and hence less beneficial arm of the UPR, is induced to a much lesser degree research is required to investigate the potential therapeutic impact of many pharmacological compounds that disrupt specific aspects of the UPR, as it also clearly serves a critical role in the replication and pathogenesis of these viral respiratory diseases. Any potential therapeutic intervention targeting the UPR would need to ensure that the balance of the impact on the host and virus is in the host's favour.