Human airway organoids model SARS-CoV-2 high infectiousness and evasion of interferon response

Abstract SARS-CoV-2 is more infectious and transmissible in humans than SARS-CoV, despite the genetic relatedness and sharing the same cellular receptor. We sought to assess whether human airway organoids can model SARS-CoV-2 infection in the human airway and elucidate the cellular basis underlying its higher transmissibility. We demonstrate that SARS-CoV-2 can establish a productive infection in human airway organoids, in which ciliated cell and basal cell are infected. Wildtype SARS-CoV-2 carrying a furin cleavage motif exhibits comparable replication kinetics to a mutant virus without the motif. Human airway organoids sustain higher replication of SARS-CoV-2 than SARS-CoV, whereas interferon response is more potently induced in the latter than the former. Overall, human airway organoids can model SARS-CoV-2 infection and recapitulate the disposable role of furin cleavage motif for virus transmission in humans. SARS-CoV-2 stealth growth and evasion of interferon response may underlie pre-symptomatic virus shedding in COVID-19 patients, leading to its high infectiousness and transmissibility.