Inhibition of SARS-CoV-2-mediated thromboinflammation by CLEC2.Fc

Abstract Thromboinflammation is the major cause of morbidity and mortality in COVID-19 patients, post-mortem examination demonstrates presence platelet-rich thrombi microangiopathy lung other visceral organs. Moreover, persistent microclots were detected both acute long COVID plasma samples. However, molecular mechanism SARS-CoV-2-induced thromboinflammation still unclear. We found that spleen tyrosine kinase (Syk)-coupled C-type lectin member 2 (CLEC2), which was highly expressed platelets, interacted with receptor-binding domain (RBD) SARS-CoV-2 spike protein (SARS-CoV-2 RBD) directly. Unlike thread-like NETs, aggregated NET formation wild-type (WT), but not CLEC2-deficient platelets. Furthermore, pseudotyped lentivirus able to induce via CLEC2, indicating RBD engaged CLEC2 activate platelets enhance formation. Administration CLEC2.Fc inhibited AAV-ACE2-infected mice. Thus, a novel pattern recognition receptor for SARS-CoV-2, promising therapeutic agent inhibit reduced risk post-acute sequelae (PASC) future. Translational Medical Research Program (AS-TM-108-02-10), Biotechnology Park Project (AS-BRPT-110-02), Academia Sinica