Trop-1/EpCAM Thr115 is a driver of hyperproliferative cell repair and of severe lung damage in COVID-19

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.