ABSTRACT
Bronchi of the upper respiratory tract are considered the site of SARSCoV- 2 infection initiation from where a possible spread to the lower respiratory tract can cause acute respiratory distress syndrome with a high degree of mortality in elderly patients. Here we established functional reconstituted primary bronchial epithelia (BE) derived from donors including both adults and children to study SARS-CoV-2 infection dynamics in a physiologically relevant model. We identified multi-ciliated cells as the primary target cells for SARS-CoV-2 in our reconstituted BE. We further observed rapid viral spread throughout the entire BE within 24-48hours. Within 3-4 days, we observed syncytia formation between ciliated cells and basal cells which accumulate at the apical side of the BE. We show that infected cells including syncytia are released into the apical lumen and contribute to the transmittable virus dose. Interestingly, some BE mainly reconstituted from young donor, showed an intrinsic resistance to infection and virus spread. This restricted infection phenotype correlated with a faster release of type-III interferon secretion. Moreover, exogenous type-III interferon treatment to permissive epithelia installed infection restriction while interferon gene knockout promoted infection. Taken together our data uncover syncytia formation as possible contribution to tissue or environmental SARS-CoV-2 dissemination and the type-III IFN response as a central contributor to SARS-CoV-2 resistance in BE, which may explain epidemiological observations that SARS-CoV-2 fatality is age dependent.