Phosphoproteomic Survey of Human iPSC-derived Lung Alveolar Type 2 Cells Reveals Cytopathogenic Host Responses to SARS-CoV-2 Infection

Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, is exerting a massive health and socioeconomic burden. The virus infects pneumocytes, also known as alveolar epithelial type 2 (AT2) cells, leading to impaired gas exchange and acute lung injury, but the mechanisms driving infection and pathology are unclear. Here, we report a quantitative phosphoproteomic time-course survey of a validated human AT2 cell model, derived from induced pluripotent stem cells (iPSCs), that reveals rapid, profound and switch-like rewiring of lung cell functional modules upon SARS-CoV-2 infection. Maladaptive responses driven by viral propagation include altered host cell signaling pathways, remodeled host translational processes, impaired RNA processing, cytoskeletal-microtubule disruption coincident with interphase arrest, and a pronounced innate immune response. Our study provides a data-rich resource that defines the native host systems hijacked by SARS-CoV-2 and potential therapeutic avenues for COVID-19.