Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe SARS-CoV-2 infection and is associated with enhanced pathogenicity and mortality. Complement hyper activation promotes lung injury and was observed in patients suffering from MERS-CoV, SARS-CoV-1 and SARS-CoV-2 infections. To evaluate the very first interactions of SARS-CoV-2 patient isolates with human epithelial tissues, 3D models of the human respiratory tract as well as lung organoids are highly suitable. © Die Autorinnen und Autoren 2022.