Jacob Bjorgen

This investigation aimed to elucidate the mechanisms of cell death contributing to the demise of alveolar type II pneumocytes in late-stage COVID-19. ATII pneumocytes are of particular interest in COVID-19 pathogenesis due to their critical role in maintaining the alveolar space structurally by engaging in the proliferative reparative response triggered by acute lung injury. COVID-19 pneumonia can be viewed as a two-stage process initiated by the infection of alveolar type I and II pneumocytes by SARS-CoV-2. The subsequent destruction of alveolar type I and II pneumocytes results in progression towards the second stage, characterized by a hyper-inflammatory immune response that drives pathology. When this project began in the summer of 2020, very little was known about the mechanisms causing hyperinflammatory lung injury in COVID-19, prompting this investigation. The role of the virus, TNF-induced necroptosis, BTK-induced pyroptosis, and PANoptosis were explored due to the reported clinical benefit of TNF and BTK inhibitors in treating COVID-19 pneumonia. The investigation made use of lung autopsy samples from four patients from Italy who had COVID-19 pneumonia. These tissues were embedded in paraffin and sectioned into slides that were analyzed using immunohistochemistry and RNAscope ISH. Images of these stains revealed that the proliferative reparative response of ATII pneumocytes contributes to the replication of SARS-CoV-2 in the lower respiratory tract by providing a significant amount of spatially contiguous susceptible cells. During the hyperinflammatory stage, we also found that cell death is driven by necroptosis, pyroptosis, and PANoptosis, all executed through a newly discovered porous latticework.