The ACE2 decoy receptor can overcome immune escape by rapid mutating SARS-CoV-2 variants and reduce cytokine induction and clot formation.

IF 9 2区 医学 Q1 CELL BIOLOGY
Ming-Shiu Lin, Tai-Ling Chao, Yu-Chi Chou, Yao Yi, Ci-Ling Chen, Kuo-Yen Huang, Sui-Yuan Chang, Pan-Chyr Yang
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引用次数: 0

Abstract

Background: The COVID-19 pandemic continues to affect the world in 2025. The rapid mutation of SARS-CoV-2 results in breakthrough infections and diminishes the efficacy of vaccines and anti-viral drugs. The severity of the disease varies across different variants, and the underlying mechanisms driving these differences remain unclear. This study explores the relationship between different Spike variants and cytotoxicity, aiming to determine whether the humanized decoy receptor ACE2-Fc can neutralize spikes from diverse variants, offering a solution to overcome rapid mutating SARS-CoV-2 induced immune escape.

Methods: We co-cultured 293 T-ACE2 cells with 293 T cells transfected with various Spike protein variants or used H1650-ACE2 cells transfected with these Spike variants. This allowed us to observe the effects of different Spike mutations, specifically focusing on cell fusion, cytotoxicity, and cytokine release from human peripheral blood mononuclear cells. Flow cytometry is employed to determine if ACE2-Fc can recognize different Spike variants. We also assess the ability of ACE2-Fc to inhibit infection, cell fusion, cytotoxicity, and cytokine release through pseudovirus infections or Spike protein transfections. Additionally, we use actual viruses from SARS-CoV-2 patients to validate the impacts of Spike mutations and the effectiveness of ACE2-Fc. Furthermore, human plasma is utilized to evaluate ACE2-Fc's capability to inhibit Spike-induced clot formation.

Results: We found that different Spike variants, particularly those with enhancements at the S2' site, increased cell-cell fusion capability, which correlated positively with cytotoxicity and cytokine IL-6 and TNF-α released from PBMCs. ACE2-Fc recognized spikes from wide-range of variants, including wild type, Alpha, Delta, Delta plus, Lambda, BA.2, BA.2.75, BA.5, BF.7, BQ.1, XBB.1, JN.1, KP.2, and KP.3, and effectively prevented these spike-expressing pseudo-viruses from entering host cells. Crucially, ACE2-Fc can prevent spike-induced cell fusion, thereby reducing subsequent cytotoxicity and the release of IL-6 and TNF-α from PBMCs. ACE2-Fc also effectively reduces plasma clot formation induced by trimeric spike proteins.

Conclusions: These findings demonstrated that ACE2-Fc could effectively combat the infection of rapidly mutating SARS-CoV-2, providing a potential solution to overcome immune evasion.

ACE2诱骗受体可以通过快速突变SARS-CoV-2变体克服免疫逃逸,减少细胞因子诱导和凝块形成。
背景:2019冠状病毒病大流行将在2025年继续影响全球。SARS-CoV-2的快速突变导致突破性感染,降低了疫苗和抗病毒药物的功效。疾病的严重程度因不同的变异而异,导致这些差异的潜在机制尚不清楚。本研究探讨了不同刺突变异与细胞毒性之间的关系,旨在确定人源化诱饵受体ACE2-Fc是否可以中和来自不同变异的刺突,为克服快速突变的SARS-CoV-2诱导的免疫逃逸提供解决方案。方法:将293 T- ace2细胞与转染了各种Spike蛋白变体的293 T细胞共培养,或使用转染了这些Spike蛋白变体的H1650-ACE2细胞。这使我们能够观察不同Spike突变的影响,特别是关注细胞融合、细胞毒性和人类外周血单核细胞的细胞因子释放。流式细胞术用于确定ACE2-Fc是否可以识别不同的Spike变体。我们还评估了ACE2-Fc通过假病毒感染或刺突蛋白转染抑制感染、细胞融合、细胞毒性和细胞因子释放的能力。此外,我们使用来自SARS-CoV-2患者的实际病毒来验证Spike突变的影响和ACE2-Fc的有效性。此外,还利用人血浆来评估ACE2-Fc抑制尖峰诱导的血栓形成的能力。结果:我们发现不同的Spike变异,特别是那些在S2位点增强的突变,增加了细胞-细胞融合能力,这与细胞毒性和细胞因子IL-6和TNF-α从pbmc释放成正相关。ACE2-Fc能识别来自野生型、Alpha、Delta、Delta plus、Lambda、BA.2、BA.2.75、BA.5、BF.7、BQ.1、XBB.1、jn1、KP.2和KP.3等多种变异的突刺,并能有效阻止这些表达突刺的伪病毒进入宿主细胞。至关重要的是,ACE2-Fc可以阻止尖峰诱导的细胞融合,从而降低随后的细胞毒性以及pbmc中IL-6和TNF-α的释放。ACE2-Fc还能有效减少三聚体刺突蛋白诱导的血浆凝块形成。结论:这些发现表明ACE2-Fc可以有效对抗快速突变的SARS-CoV-2的感染,为克服免疫逃避提供了潜在的解决方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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