Human iPSC-derived airway models enable comparative analysis of SARS-CoV-2 infection in healthy and COPD bronchial epithelium.

SARS-CoV-2 causes severe and persistent lower respiratory tract infections, yet human models that recapitulate long-term tissue responses are limited. Here, we used a human induced pluripotent stem cell (hiPSC)-derived bronchial airway models (iALI) to investigate SARS-CoV-2 infection in healthy and COPD-derived tissues. Infection of iALI led to robust viral replication, persistent infection, cilia loss in infected ciliated epithelial cells, increased mucus secretion, and higher inflammatory cytokine release in COPD iALI. Notably, healthy iALI displayed a delayed innate immune response, whereas COPD iALI exhibited an earlier and stronger response, characterized by elevated IL-2, CCL5, G-CSF, and CXCL10 secretion, along with reduced sensitivity to antiviral treatment. These findings reveal donor-specific differences in bronchial epithelial responses to SARS-CoV-2 and establish iALI culture models as a powerful platform for studying long-term respiratory viral infections in both healthy and diseased contexts, especially COPD.