A new study using cells, transgenic mouse models, and cultured human lung tissue provides evidence that the ability to trigger programmed cell death (apoptosis) may enable highly pathogenic coronaviruses to spread within their hosts so successfully. Targeting this process may reduce the severity of coronavirus diseases, the study goes on to show. While scientists have been aware that highly pathogenic coronaviruses leave substantial cell death in their wake as they infiltrate the body, the importance of apoptosis to the internal spread of coronavirus infections - and the underlying mechanisms that account for the virus' high pathogenicity - have not been clear. To fill this research gap, Hin Chu and colleagues first observed MERS-CoV in cultured human lung tissue and in the lungs of infected transgenic mice, finding that the virus induced substantial apoptosis. To explore how the virus triggered programmed cell death in its host organ's cells, the researchers analyzed the mRNA transcripts of human bronchial epithelial cells at 12 and 24 hours after infection with MERS-CoV, finding that genes regulated by the protein kinase R-like endoplasmic reticulum kinase (PERK), which are associated with cell death, were highly expressed. When Chu et al. inhibited PERK signaling in the infected human lung tissues, they saw substantial reductions in both the cell-to-cell spread of MERS-CoV and in cell death induced by the virus. The researchers also performed tests in which they inhibited PERK signaling in transgenic mice infected with the virus. This treatment down-regulated genes involved in apoptosis and reduced lung damage. While the authors found that PERK inhibitors did not suppress apoptosis triggered by SARS-CoV or SARS-CoV-2, they did observe that an intrinsic apoptosis inhibitor effectively suppressed the process in mice infected with either SARS-CoV or SARS-CoV-2 and reduced lung damage from SARS-CoV-2. These findings suggest that while the three highly pathogenic human coronaviruses - SARS-CoV, MERS-CoV, and SARS-CoV-2 - may trigger apoptosis through different mechanisms, inhibiting apoptosis may attenuate the pathogenesis of all three.