Lameire, S.; Debeuf, N.; Deckers, J.; De Wolf, C.; Vanheerswynghels, M.; Toussaint, W.; De Vlieger, L.; Van Hoecke, L.; De Cae, S.; Schepens, B.; Vanhee, S.; Lambrecht, B. N.

Given the ongoing evolution of SARS-CoV-2 and the historical emergence of other highly transmissible coronaviruses like SARS-CoV and HCoV-NL63, in vivo coronavirus research remains crucial even when the COVID-19 pandemic is receding. Due to restricted tropism of SARS-CoV-2 and other coronaviruses for mouse cells, model systems of infection rely on transgenic expression of the entry receptor human ACE2 (hACE2). Available hACE2 transgenic models using the Krt18 promotor express the receptor across multiple cell types and organ systems, leading to multiple disease features including pneumonia, vascular compromise and neuro-inflammation, that reflect the multi-organ nature of COVID-19. To disentangle the role of cell tropism in driving the clinical manifestations of the disease, we generated two new transgenic mouse models, Sftpa1-hACE2 and Cdh5-hACE2 transgenic mice, with hACE2 restricted to lung epithelium or endothelial cells respectively. In Sftpa1-hACE2 mice, with high expression of the hACE2 receptor in lung alveolar type 2 cells, SARS-CoV-2 infection led to rapidly progressing disease, characterised by a strong neutrophilic innate immune response in the lung, followed by viral neuro-invasion and early death. Krt18-hACE2 mice additionally recruited various dendritic cell subsets and gradually developed adaptive immunity. In Cdh5-hACE2 Tg mice with exclusive endothelial tropism of the virus, viral inoculation via the lung or systemic circulation did not lead to viral propagation or disease manifestations, despite endothelial expression of hACE2 in the lung. These results suggest that tropism for alveolar epithelial cells increases disease severity, while endothelial cell tropism per se does not drive the vascular consequences often seen in COVID-19 patients. Our new transgenic mouse models will be helpful to dissect how cell tropism contributes to the clinical manifestations of coronavirus infection.