The Role of Thrombomodulin in Diseases / 中国生物化学与分子生物学报

Thrombomodulin (TM) is a single-chain transmembrane glycoprotein that mainly exists in vascular endothelial cells, hematopoietic progenitor cells, monocytes and macrophages. TM is mainly composed of five structural regions: the N-terminal lectin-like domain which plays a role in anti-inflammatory, and the six epidermal growth factor-like repeats which function as coagulation and fibrinolysis as well as serine-rich threonine regions and transmembrane domains and cytoplasmic domains. TM exhibits anti-inflammatory and anticoagulant effects by binding to thrombin to activate protein C, and TM-thrombin complex can also activate fibrinolytic inhibitors to suppress fibrinolysis. Previous reports showed that inhibiting epithelial mesenchymal transformation, mitogen-activated protein kinase or activating protein C and fibrinolytic inhibitor are the major mechanisms by which TM exerts anti-tumor properties. In atherosclerosis, TM can prevent atherosclerosis by blocking the activation of thrombin-mediated PAR-1 and inhibiting autophagy and apoptosis of endothelial cells. TM lectin-like domains can also bind to thrombin to inhibit its activity and further inhibit pulmonary thrombosis, fibrosis and inflammation. Moreover, TM protein is also involved in the pathogenesis of diabetic nephropathy, preeclampsia and ischemia-reperfu-sion injury. At present, TM is only clinically used for the treatment of sepsis and disseminated intravascular coagulation. Its role and therapeutic potential in cardiovascular and cerebrovascular diseases, cancers and other diseases deserve further exploration.

The immunodominant and neutralization linear epitopes for SARS-CoV-2

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) becomes a tremendous threat to global health. Although vaccines against the virus are under development, the antigen epitopes on the virus and their immunogenicity are poorly understood. Here, we simulated the three-dimensional structures of SARS-CoV-2 proteins with high performance computer, predicted the B cell epitopes on spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins of SARS-CoV-2 using structure-based approaches, and then validated the epitope immunogenicity by immunizing mice. Almost all 33 predicted epitopes effectively induced antibody production, six of which were immunodominant epitopes in patients identified via the binding of epitopes with the sera from domestic and imported COVID-19 patients, and 23 were conserved within SARS-CoV-2, SARS-CoV and bat coronavirus RaTG13. We also found that the immunodominant epitopes of domestic SARS-CoV-2 were different from that of the imported, which may be caused by the mutations on S (G614D) and N proteins. Importantly, we validated that eight epitopes on S protein elicited neutralizing antibodies that blocked the cell entry of both D614 and G614 pseudo-virus of SARS-CoV-2, three and nine epitopes induced D614 or G614 neutralizing antibodies, respectively. Our present study shed light on the immunodominance, neutralization, and conserved epitopes on SARS-CoV-2 which are potently used for the diagnosis, virus classification and the vaccine design tackling inefficiency, virus mutation and different species of coronaviruses.