SARS-CoV-2 RBD and Its Variants Can Induce Platelet Activation and Clearance:Implications for Antibody Therapy and Vaccinations against COVID-19

扫码查看

原文链接

NETL
NSTL
万方数据

外文摘要：The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health burden.Severe cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia(VITT)are both associated with thrombosis and thrombocytopenia;however,the underlying mechanisms remain inadequately understood.Both infection and vaccination utilize the spike protein receptor-binding domain(RBD)of SARS-CoV-2.We found that intravenous injection of recombinant RBD caused significant platelet clearance in mice.Further investigation revealed the RBD could bind platelets,cause platelet activation,and potentiate platelet aggregation,which was exacerbated in the Delta and Kappa variants.The RBD-platelet interaction was partially dependent on the β3 integrin as binding was significantly reduced inβ3-/-mice.Furthermore,RBD binding to human and mouse platelets was significantly reduced with related αⅡbβ3 antagonists and mutation of the RGD(arginine-glycine-aspartate)integrin binding motif to RGE(arginine-glycine-glutamate).We developed anti-RBD polyclonal and several monoclonal antibodies(mAbs)and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation,aggregation,and clearance in vivo,and SARS-CoV-2 infection and replication in Vero E6 cells.Our data show that the RBD can bind platelets partially though αⅡbβ3 and induce platelet activation and clearance,which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and VITT.Our newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.

作者：

Xiaoying Ma、Jady Liang、Guangheng Zhu、Preeti Bhoria、Aron A.Shoara、Daniel T.MacKeigan、Christopher J.Khoury、Sladjana Slavkovic、Lisha Lin、Danielle Karakas、Ziyan Chen、Viktor Prifti、Zhenze Liu、Chuanbin Shen、Yuchong Li、Cheng Zhang、Jiayu Dou、Zack Rousseau、Jiamin Zhang、Tiffany Ni、Xi Lei、Pingguo Chen、Xiaoyu Wu、Hamed Shaykhalishahi、Samira Mubareka、Kim A.Connelly、Haibo Zhang、Ori Rotstein、Heyu Ni

展开 >

作者单位：

Department of Laboratory Medicine and Pathobiology,University of Toronto,Toronto,ON,Canada

Department of Laboratory Medicine,Keenan Research Centre for Biomedical Science of St.Michael's Hospital,Toronto,ON,Canada

Toronto Platelet Immunobiology Group,Toronto,ON,Canada

Department of Physiology,University of Toronto,Toronto,ON,Canada

CCOA Therapeutics Inc.,Toronto,ON,Canada

Canadian Blood Services Centre for Innovation,Toronto,ON,Canada

The State Key Laboratory of Respiratory Disease,Guangzhou Institute of Respiratory Disease,The First Affiliated Hospital of Guangzhou Medical University,Guangzhou,Guangdong,China

Department of Laboratory Medicine,The Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou,China

Advanced Pharmaceutics &Drug Delivery Laboratory,Leslie Dan Faculty of Pharmacy,University of Toronto,Toronto,ON,Canada

Department of Medical Microbiology and Infectious Disease,Sunnybrook Health Science Centre,Toronto,ON,Canada

Department of Medicine,University of Toronto,Toronto,ON,Canada

Division of Cardiology,St.Michael's Hospital,Toronto,ON,Canada

Department of Anesthesiology and Pain Medicine and Division of Critical Care Medicine,University of T

Department of Surgery,University of Toronto,Toronto,ON,Canada

展开 >

出版年：

2024

DOI：

10.34133/research.0124

研究(英文)

CSTPCD

ISSN：

年,卷(期)：2024.2024(3)