Human lung stem cell-based alveolospheres provide insights into SARS-CoV-2 mediated interferon responses and pneumocyte dysfunction

Katsura, Hiroaki; Sontake, Vishwaraj; Tata, Aleksandra; Kobayashi, Yoshihiko; Edwards, Caitlin E.; Heaton, Brook E.; Konkimalla, Arvind; Asakura, Takanori; Mikami, Yu; Fritch, Ethan J.; Lee, Patty J.; Heaton, Nicholas S.; Boucher, Richard C.; Randell, Scott H.; Baric, Ralph S.; Tata, Purushothama Rao

Coronavirus infection causes diffuse alveolar damage leading to acute respiratory distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering an understanding of COVID-19 pathogenesis. We report a feeder-free, scalable, chemically-defined, and modular alveolosphere culture system for propagation and differentiation of human alveolar type 2 cells/pneumocytes derived from primary lung tissue. Cultured pneumocytes express the SARS-CoV-2 receptor ACE2 and can be infected with virus. Transcriptome and histological analysis of infected alveolospheres mirrors features of COVID-19 lungs, including emergence of interferon mediated inflammatory responses, loss of surfactant proteins, and apoptosis. Treatment of alveolospheres with interferons recapitulates features of virus infection, including cell death. In contrast, alveolospheres pretreated with low dose IFNs show a reduction in viral replication, suggesting the prophylactic effectiveness of IFNs against SARS-CoV-2. Human stem cell-based alveolospheres thus provide novel insights into COVID-19 pathogenesis and can serve as a model for understanding human respiratory diseases.