Human airway lineages derived from pluripotent stem cells reveal the epithelial responses to SARS-CoV-2 infection

Wang, Ruobing; Hume, Adam J.; Beermann, Mary Lou; Simone-Roach, Chantelle; Lindstrom-Vautrin, Jonathan; Suer, Jake Le; Huang, Jessie; Olejnik, Judith; Villacorta-Martin, Carlos; Bullitt, Esther; Hinds, Anne; Ghaedi, Mahboobe; Werder, Rhiannon B.; Abo, Kristine M.; Wilson, Andrew A.; Mühlberger, Elke; Kotton, Darrell N.; Hawkins, Finn J.

There is an urgent need to understand how SARS-CoV-2 infects the airway epithelium and in a subset of individuals leads to severe illness or death. Induced pluripotent stem cells (iPSCs) provide a near limitless supply of human cells that can be differentiated into cell types of interest, including airway epithelium, for disease modeling. We present a human iPSC-derived airway epithelial platform, composed of the major airway epithelial cell types, that is permissive to SARS-CoV-2 infection. Subsets of iPSC-airway cells express the SARS-CoV-2 entry factors ACE2 and TMPRSS2. Multiciliated cells are the primary initial target of SARS-CoV-2 infection. Upon infection with SARS-CoV-2, iPSC-airway cells generate robust interferon and inflammatory responses and treatment with remdesivir or camostat methylate causes a decrease in viral propagation and entry, respectively. In conclusion, iPSC-derived airway cells provide a physiologically relevant in vitro model system to interrogate the pathogenesis of, and develop treatment strategies for, COVID-19 pneumonia. Highlights and eTOC blurb Subsets of human iPSC-airway epithelial cells express SARS-Co-V entry factors ACE2 and TMPRSS2. iPSC-airway cells are permissive to SARS-CoV-2 infection via multiciliated cells. SARS-CoV-2 infection of iPSC-airway leads to a robust interferon and inflammatory response. iPSC-airway is a physiologically relevant model to study SARS-CoV-2 infection.