ABSTRACT
Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 invades cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). While several attachment factors and co-receptors for SARS-CoV-2 have been identified, the complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics. Here, we identified butyrophilin subfamily 3 member A2 (BTN3A2) as a potent inhibitor of SARS-CoV-2 infection. The mRNA level of BTN3A2 was correlated with COVID-19 severity. Upon re-analysis of a human lung single-cell RNA sequencing dataset, BTN3A2 expression was predominantly identified in epithelial cells. Moreover, this expression was elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same cellular subtypes in the lung. Additionally, BTN3A2 primarily targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through direct interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. Furthermore, BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in a BTN3A2 transgenic mouse model. These results reveal a key role of BTN3A2 in the fight against COVID-19 and broaden our understanding of the pathobiology of SARS-CoV-2 infection. Identifying potential monoclonal antibodies that target BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19.