1. Enhancement of NETosis by ACE2-cross-reactive anti-SARS-CoV-2 RBD antibodies in patients with COVID-19.
- Author
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Hsieh, Kun-Han, Chao, Chiao-Hsuan, Cheng, Yi-Ling, Lai, Yen-Chung, Chuang, Yung-Chun, Wang, Jen-Ren, Chang, Sui-Yuan, Hung, Yuan-Pin, Chen, Yi-Ming, Liu, Wei-Lun, Chuang, Woei-Jer, and Yeh, Trai-Ming
- Subjects
Anti-ACE2 autoantibody ,COVID-19 ,Cross-reactivity ,NETosis ,Thrombosis ,Humans ,Animals ,Mice ,COVID-19 ,SARS-CoV-2 ,Angiotensin-Converting Enzyme 2 ,COVID-19 Vaccines ,Dasatinib ,Immunoglobulin G ,Autoantibodies ,Spike Glycoprotein ,Coronavirus ,Protein Binding - Abstract
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.
- Published
- 2024