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研究生： 謝坤翰
Hsieh, Kun-Han
論文名稱： 探討具血管收縮素轉化酶2交叉反應性抗新型冠狀病毒棘蛋白受體結合域抗體在嚴重特殊傳染性肺炎患者中對於釋網凋亡的增強作用
Study on the enhancement of NETosis by ACE2-cross-reactive anti-SARS-CoV-2 RBD antibodies in patients with COVID-19
指導教授： 葉才明
Yeh, Trai-Ming
學位類別： 碩士
Master
系所名稱： 醫學院 - 醫學檢驗生物技術學系
Department of Medical Laboratory Science and Biotechnology
論文出版年： 2024
畢業學年度： 112
語文別： 中文
論文頁數： 93
中文關鍵詞： 嚴重特殊傳染性肺炎 、抗人類血管收縮素轉化酶2自體抗體 、嗜中性球胞外陷阱 、交叉反應 、血栓形成
外文關鍵詞： COVID-19, anti-ACE2 autoantibody , NETosis, cross-reactivity, thrombosis
ORCID： 0009-0005-7402-7622
相關次數： 點閱：75  下載：4 
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    • 大量形成的嗜中性球胞外陷阱(NETs, or NETosis)和高水平的自體抗體與嚴重特殊傳染性肺炎(COVID-19)患者的不良預後和疾病嚴重程度有關。 據報導，具人類血管收縮素轉化酶2 (ACE2)交叉反應性抗嚴重急性呼吸症候群冠狀病毒2棘蛋白受體結合域(SARS-CoV-2 RBD)抗體(CR Abs)是抗ACE2自體抗體的來源之一。然而，CR Abs在NETs形成中的病理意義仍然未知。在本研究中，我們首先透過血清學分析評估了不同嚴重程度的COVID-19患者血清中CR抗體產生的程度。接著透過測試CR Abs陽性的COVID-19患者血清和純化IgG以及小鼠單株CR抗體 (mAb 127)，以了解它們對NETosis的影響，並研究其可能的病理機制。在120名患者中發現CR抗體含量與COVID-19嚴重程度之間存在關聯。在存在RBD的情況下，來自重症COVID-19患者的CR Abs陽性血清和IgG以及mAb 127顯著激活人類白血球並引發NETosis。這種 CR Ab和RBD共存引發的NETosis進一步活化了參與血栓形成的相關細胞，但當CR Ab與ACE2或Fc受體之間的相互作用被破壞時，NETosis就會消除。我們也發現，在存在重組ACE2或Src家族激酶抑制劑(dasatinib)的情況下，CR Abs誘導的NETosis會受到抑制。此外，我們發現COVID-19疫苗接種不僅可以降低COVID-19的嚴重程度，還可以阻止 SARS-CoV-2 感染後CR抗體的產生。我們的研究結果指出CR Abs可以透過增強NETosis而加劇COVID-19病症的可能致病作用，強調ACE2和dasatinib作為潛在的治療方法，並支持疫苗接種在降低COVID-19患者疾病嚴重程度和CR Abs產生方面的益處。

    Neutrophil extracellular trap (NETs) formation or NETosis and autoantibodies are related to poor prognosis and disease severity in 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. 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. 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. 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.

    中文摘要 II Abstract III Table of Contents IV 1. Introduction 1 1.1 COVID-19 1 1.1.1 Epidemiology 1 1.1.2 COVID-19 symptoms and complications 2 1.2 SARS-CoV-2 2 1.2.1 Phylogeny, taxonomy, and transmission 2 1.2.2 Viral genome and proteins 3 1.2.3 Viral entry 3 1.2.4 Viral replication and budding 4 1.3 Innate Immune Response 5 1.3.1 Inflammation in COVID-19 5 1.3.2 Neutrophil activation in COVID-19 6 1.3.3 NETosis in COVID-19 7 1.4 Adaptive Immune Response 8 1.4.1 Antibody Response in COVID-19 8 1.4.2 Autoantibodies in COVID-19 9 1.4.3 Anti-ACE2 Autoantibodies in COVID-19 10 2. Research goal and specific aims 11 3. Materials and Methods 13 3.1 Material Reagents and Instrument Usage 13 3.1.1 Cell lines 13 3.1.2 Antibodies 13 3.1.3 Recombinant protein 14 3.1.4 Reagents 14 3.1.5 Instruments 16 3.2 Isolation of human leukocytes 16 3.3 Isolation of human peripheral blood mononuclear cells 16 3.4 Isolation of human neutrophils 17 3.5 Isolation of human platelets 17 3.6 Complement-dependent cytotoxicity assay 18 3.7 Lactate dehydrogenase activity assay 18 3.8 Western blotting 18 3.9 Recombinant SARS-CoV-2 S1-RBD protein generation 19 3.10 Monoclonal antibody and F(ab')2 fragment generation 20 3.11 Indirect ELISAs 20 3.12 In vitro human leukocyte stimulation 20 3.13 Neutrophil adhesion assay 21 3.14 Quantification of NET formation 21 3.15 NET purification and treatment with NET-containing supernatants 22 3.16 Endothelial cell permeability assay 23 3.17 Flow cytometry analysis of platelet activation 23 3.18 HUVEC, neutrophil and platelet coculture model 23 3.19 Cohort Information 24 3.20 Serum preadsorption assay 25 3.21 Purification and preadsorption of immunoglobulin G (IgG) from COVID-19 patient serum 25 3.22 Statistical analysis 26 4. Results 27 4.1. mAb 127 induces complement-dependent cytotoxicity (CDC) in ACE2-overexpressing HEK 293 cells 27 4.2. mAb 127 induces leukocyte activation in the presence of RBD protein 27 4.3. mAb 127 stimulates neutrophil activation in the presence of RBD protein 28 4.4. mAb 127 triggers NETosis in the presence of RBD protein 29 4.5. NETs from activated neutrophils drive thrombosis-associated cell activation in vitro 29 4.6. Both ACE2 and the Fc receptor are needed for ACE2-cross-reactive anti-RBD antibodies to trigger NETosis 30 4.7. Src- and PAD-4-dependent pathways are involved in ACE2 cross-reactive anti-RBD antibody-induced NETosis in the presence of RBD 31 4.9. Vaccination prevents the production of ACE2 cross-reactive anti-RBD antibodies in COVID-19 32 4.10. Patients’ sera with CR Abs induce leukocyte activation in the presence of RBD protein 33 4.11. Patients’ sera with CR Abs induce IL-8 secretion and NET formation in human neutrophils in the presence of RBD protein 34 4.12. Purified CR IgG from patients with COVID-19 induces NETosis in the presence of RBD protein 34 5. Discussion 36 6. References 41 7. Tables 48 8. Figures 50

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