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

Programmed cell death is a fundamental process to maintain the homeostasis by eliminating the dead and unwanted cells. Depending on the proteins involved, programmed cell death can have different forms, such as apoptosis, necroptosis, and pyroptosis. Apoptosis is a silent, non-lytic way of cell death, while necroptosis and pyroptosis are inflammatory processes that require the participance of pore-forming proteins. The pore-forming proteins creates pores on plasma membrane to facilitate the release of cellular contents. Each cell death process plays a critical role in distinct physiological and pathological conditions, specifically in viral infections. Programmed cell death process is commonly viewed separately, but emerging evidence supports the idea of intensive interplay between cell death processes. And a concept termed PANoptosis was introduced to explain the interplay.This dissertation mainly focuses on the multiple cell death responses triggered by SARS-CoV-2, the virus causing the COVID-19 pandemic. Using various models, we reported that SARS-CoV-2 induced both necroptosis and apoptosis in lung epithelial cells. And SARS-CoV-2 induced necroptosis was predominantly in the virus infected cells, while apoptosis can be induced in either infected or bystander cells. With the virus titration experiment, we were able to delineate the response of necroptosis and apoptosis as apoptosis was mostly activated in bystander uninfected cells. In addition, we observed that the number of cells executing necroptosis was much higher than the number of cells executing apoptosis. This suggests necroptosis is not just a direct cell death consequence of SARS-CoV-2 infection, it is also the dominant cell death consequence. Further, we found that Z-DNA binding protein (ZBP1) was induced during SARS-CoV-2 infection, and its ligand, Z-RNA, was detected in SARS-CoV-2 infected cells. We then confirmed the interaction between the two by proximity ligation assay. Finally, we compared the cell death responses against different variants of concern (VOC), and found the Delta variant triggered more robust cell death response in both cell line and animals.These intriguing findings reveal novel distribution patterns of necroptosis and apoptosis during viral infection and expand our understanding of the complex interplay between different cell death processes.