Margherita Baldassarri, Marco Trerotola, Giulia Brunelli, Noemi La Francesca, Laura Bergantini, Benedetta Tella, Giulia Rollo, Cecilia Altemura, Vera Giacomazzi, Emanuela Guerra, Martina Ceci, Ludovica Pantalone, Samantha Minetto, Elena Bargagli, Cristoforo Pomara, Rossano Lattanzio, Antonino Moschella, Federica Maria Previtera, Cristiana Bellan, Network for Italian Genomes, GEN-COVID Multicenter Study, Alessandra Renieri, Chiara Fallerini, Saverio Alberti
SARS-CoV-2 lung infection triggers an acute reaction that can severely impair oxygen exchange. However, the underlying molecular processes are poorly understood. The TROP1/EPCAM p.M115T polymorphism was found associated with COVID-19 severity. We discovered here that the T115 Trop-1/EpCAM is a driver of cell growth, whereas M115 Trop-1/EpCAM has little, if any, cell growth induction capacity. TROP1/EPCAM knockout mice showed altered proliferation of embryonic stem cells. The Trop-1/EpCAM T115 allele was then found to drive hyperproliferative capacity in murine fibrosarcoma cells. Corresponding growth stimulation was shown in human colon cancer cells, through CRISPR-Cas9 ablation of the endogenous TROP1/EPCAM and comparative transfection of TROP1/EPCAM p.T115 (T-mod) or p.M115 (M-mod) alleles. In COVID-19 patients, T115 Trop-1/EpCAM was shown to cause aberrant, hyperproliferative wound repair in SARS-CoV-2-damaged lung alveoli that led to critical oxygen-exchange impairment. Analysis of COVID-19 patient lungs at autopsy showed hyperproliferation of T115 Trop-1/EpCAM+ epithelial cells over the alveolar epithelium damaged by the infection. This correlated with T115 Trop-1/EpCAM+ inflammatory cells hyperproliferation and alveolar hyaline membrane formation. These multi-layered barriers were computed to reduce oxygen diffusion by up to 100-fold. Our findings indicate an unanticipated mechanism for lung damage by T115 Trop-1/EpCAM, and suggest a potential target for corresponding therapeutic approaches.