Determinants of the tropism of SARS-CoV-2 and other coronaviruses in 3D models of human lung epithelia

The reasons for the severity of infection with SARS-CoV-2, a virus that induces a case fatality rate greater than 1% in symptomatic patients, are not understood. Pathological data indicate that this virus infects the respiratory tract and pulmonary alveoli, which likely contributes to the severe pneumonia characteristic of COVID-19 syndrome. However, the determinants responsible for this tropism and the precise nature of the target cells in the human respiratory tract remain to be explored. For this purpose, we propose to use 3D culture systems that mimic the architecture, cell composition and functions of pulmonary epithelia. We will compare the tropism of SARS-CoV-2 and more benign human coronaviruses for primary epithelia of the upper and lower respiratory tract, to determine whether the tropism is associated with pathogenicity. We will use models based on human airway epithelia reconstructed with fully differentiated hair cells, which can express high levels of coronavirus entry cofactors. We will also take advantage of "lung-on-a-chip" technology that mimics lung alveolar stretching associated with breathing to develop physiologically relevant models of SARS-CoV-2 infection.