- 作者: Kun-Han Hsieh, Chiao-Hsuan Chao, Yi-Ling Cheng, Yen-Chung Lai, Yung-Chun Chuang, Jen-Ren Wang, Sui-Yuan Chang, Yuan-Pin Hung, Yi-Ming Arthur Chen, Wei-Lun Liu, Woei-Jer Chuang & Trai-Ming Yeh
- 作者服務機構: 1.Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan 2.Data Science Center, College of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan 3.Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 4.Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan 5.Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan 6.Department of Critical Care Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, 243, Taiwan 7.Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA 8.Department of Internal Medicine, National Cheng Kung University, Medical College and Hospital, Tainan, Taiwan 9.Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan 10.Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan 11.Department of Medical Laboratory and Regenerative Medicine, MacKay Medical College, New Taipei, Taiwan 12.Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 13.Diseases and Vaccinology, National Institute of Infectious National Health Research Institutes, Miaoli County, 350, Taiwan 14.Diseases and Vaccinology, National Institute of Infectious National Health Research Institutes, Tainan, Taiwan 15.Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA 16.Laboratory of Important Infectious Diseases and Cancer, Department of Medicine, School of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan 17. Leadgene Biomedical, Inc, Tainan, Taiwan 18.School of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan
- 中文摘要:
- 英文摘要:
Background
High levels of neutrophil extracellular trap (NET) formation or NETosis and autoantibodies are related to poor prognosis and disease severity of COVID-19 patients. Human angiotensin-converting enzyme 2 (ACE2) cross-reactive anti-severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain (SARS-CoV-2 RBD) antibodies (CR Abs) have been reported as one of the sources of anti-ACE2 autoantibodies. However, the pathological implications of CR Abs in NET formation remain unknown.
Methods
In this study, we first assessed the presence of CR Abs in the sera of COVID-19 patients with different severity by serological analysis. Sera and purified IgG from CR Abs positive COVID-19 patients as well as a mouse monoclonal Ab (mAb 127) that can recognize both ACE2 and the RBD were tested for their influence on NETosis and the possible mechanisms involved were studied.
Results
An association between CR Abs levels and the severity of COVID-19 in 120 patients was found. The CR Abs-positive sera and IgG from severe COVID-19 patients and mAb 127 significantly activated human leukocytes and triggered NETosis, in the presence of RBD. This NETosis, triggered by the coexistence of CR Abs and RBD, activated thrombus-related cells but was abolished when the interaction between CR Abs and ACE2 or Fc receptors was disrupted. We also revealed that CR Abs-induced NETosis was suppressed in the presence of recombinant ACE2 or the Src family kinase inhibitor, dasatinib. Furthermore, we found that COVID-19 vaccination not only reduced COVID-19 severity but also prevented the production of CR Abs after SARS-CoV-2 infection.
Conclusions
Our findings provide possible pathogenic effects of CR Abs in exacerbating COVID-19 by enhancing NETosis, highlighting ACE2 and dasatinib as potential treatments, and supporting the benefit of vaccination in reducing disease severity and CR Abs production in COVID-19 patients. - 中文關鍵字:
- 英文關鍵字: COVID-19, Anti-ACE2 autoantibody, NETosis, Cross-reactivity, Thrombosis