Unraveling the cell death induced by SARS-CoV-2 in lung epithelial cells

Abstract The COVID-19 pandemic has continued to affect people’s lives worldwide, and SARS-CoV-2, the pathogen that causes the pandemic, has infected over 100 million people and claimed over 10 million lives globally. There is strong evidence that lung damage contributes to the inflammatory responses against SARS-CoV-2, and that diverse forms of cell death occur in myeloid cells upon infection. However, less is known about the cell death pathways activated in the primary cell target of SARS-CoV-2, lung epithelial cells. Previously, we showed that conventional pyroptosis was activated in bystander myeloid cells. Using a human epithelial cell line with the ACE2 receptor and primary human airway epithelial culture, we analyzed the impact of SARS-CoV-2 infection on cell death. The latter is grown at an air-liquid interface (ALI) and is used to model airway pseudostratified epithelium. SARS-CoV-2 infection of these cells triggers lytic cell death. Pathway analysis shows that biomarkers of necroptosis, apoptosis, and pyroptosis are activated and increase with time, but some forms of cell death are limited predominantly to cells that are co-stained with SARS-CoV-2 viral antigens while others are not. RT-PCR and single-cell RNAseq analysis revealed that cell death genes increase with high viral titer and severity of disease in patients. R56 AI158314, R01 AI158314, AI029564, AI141333, CA232109