Details

Autor(en) / Beteiligte

• Sung, Pei‐Shan
• Sun, Cheng‐Pu
• Tao, Mi‐Hua
• Hsieh, Shie‐Liang

Titel

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

Ist Teil von

• EMBO molecular medicine, 2023-07, Vol.15 (7), p.e16351-n/a

Ort / Verlag

England: EMBO Press

Erscheinungsjahr

2023

Quelle

Access via Wiley Online Library

Beschreibungen/Notizen

• Thromboinflammation is the major cause of morbidity and mortality in COVID‐19 patients, and post‐mortem examination demonstrates the presence of platelet‐rich thrombi and microangiopathy in visceral organs. Moreover, persistent microclots were detected in both acute COVID‐19 and long COVID plasma samples. However, the molecular mechanism of SARS‐CoV‐2‐induced thromboinflammation is still unclear. We found that the spleen tyrosine kinase (Syk)‐coupled C‐type lectin member 2 (CLEC2), which was highly expressed in platelets and alveolar macrophages, interacted with the receptor‐binding domain (RBD) of SARS‐CoV‐2 spike protein (SARS‐CoV‐2 RBD) directly. Unlike the thread‐like NETs, SARS‐CoV‐2‐induced aggregated NET formation in the presence of wild‐type (WT), but not CLEC2‐deficient platelets. Furthermore, SARS‐CoV‐2 spike pseudotyped lentivirus was able to induce NET formation via CLEC2, indicating SARS‐CoV‐2 RBD engaged CLEC2 to activate platelets to enhance NET formation. Administration of CLEC2.Fc inhibited SARS‐CoV‐2‐induced NET formation and thromboinflammation in AAV‐ACE2‐infected mice. Thus, CLEC2 is a novel pattern recognition receptor for SARS‐CoV‐2, and CLEC2.Fc and may become a promising therapeutic agent to inhibit SARS‐CoV‐2‐induced thromboinflammation and reduced the risk of post‐acute sequelae of COVID‐19 (PASC) in the future. Synopsis CLEC2 interacts with SARS‐CoV‐2 spike RBD and is critical for SARS‐CoV‐2‐induced lung injury. In the presence of platelets, SARS‐CoV‐2 induces robust NET formation and cytokine release, while administration of CLEC2.Fc prevents platelet‐mediated enhancement of NET formation and cytokine storm via blocking interactions between CLEC2 and SARS‐CoV‐2 spike protein. CLEC2 interacts with SARS‐CoV‐2 Spike RBD of wild type, alpha, beta, gamma, delta, and omicron, but not with SARS‐CoV Spike RBD. SARS‐CoV‐2 Spike RBD activates platelet via CLEC2 inducing aggregated NET formation. SARS‐CoV‐2 upregulates the expression of podoplanin in the lungs after infection. Recombinant CLEC2.Fc inhibits SARS‐CoV‐2‐induced thromboinflammation in the lungs and heart. Recombinant CLEC2.Fc attenuates SARS‐CoV‐2‐induced NET formation and collagen deposition in the lungs. CLEC2 interacts with SARS‐CoV‐2 spike RBD and is critical for SARS‐CoV‐2‐induced lung injury. In the presence of platelets, SARS‐CoV‐2 induces robust NET formation and cytokine release, while administration of CLEC2.Fc prevents platelet‐mediated enhancement of NET formation and cytokine storm via blocking interactions between CLEC2 and SARS‐CoV‐2 spike protein.