Cadherin 1 negatively regulates SARS-CoV-2 infection in the olfactory epithelium

Olfactory dysfunction is a major symptom of COVID-19 syndrome. The critical genes contributing to SARS-CoV-2 infection are not fully understood. Here, we identified Cadherin 1 (CDH1), a hub in the interaction network of viral entry-related genes in human and mouse olfactory epithelium (OE), is coexpressed with ACE2 in sustentacular cells. CDH1 overexpression attenuates pseudoviral and authentic SARS-CoV-2 infection in ACE2-expressing HEK293T cells and human OE organoids, whereas CDH1 downregulation promotes infection. Mechanistically, CDH1 interacts with ACE2 and competes with the Spike protein for ACE2 binding. Three residues in CDH1 (W59, N168, and Q197) are critical for CDH1-ACE2 binding, and mutations at these residues weaken the interaction and enhance pseudoviral infection. In the OE of deceased COVID-19 patients, cells with higher viral load exhibit lower CDH1 expression. This inverse correlation between CDH1 expression and SARS-CoV-2 load is validated in human bronchial epithelial cells, and in lung ciliated and secretory cells. Collectively, our findings establish CDH1 as a novel restriction factor for SARS-CoV-2 infection in the olfactory system, potentially offering a target for antiviral therapy.