Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United States.
Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, United States.
Front Immunol. 2022 Jun 10;13:918881. doi: 10.3389/fimmu.2022.918881. eCollection 2022.
Angiotensin Converting Enzyme 2 (ACE2) is the primary cell entry receptor for SARS-CoV and SARS-CoV-2 viruses. A disintegrin and metalloproteinase 17 (ADAM17) is a protease that cleaves ectodomains of transmembrane proteins, including that of ACE2 and the proinflammatory cytokine TNF-α, from cell surfaces upon cellular activation. We hypothesized that blockade of ADAM17 activity would alter COVID-19 pathogenesis. To assess this pathway, we blocked the function of ADAM17 using the monoclonal antibody MEDI3622 in the K18-hACE2 transgenic mouse model of COVID-19. Antibody-treated mice were healthier, less moribund, and had significantly lower lung pathology than saline-treated mice. However, the viral burden in the lungs of MEDI3622-treated mice was significantly increased. Thus, ADAM17 appears to have a critical anti-viral role, but also may promote inflammatory damage. Since the inflammatory cascade is ultimately the reason for adverse outcomes in COVID-19 patients, there may be a therapeutic application for the MEDI3622 antibody.
血管紧张素转化酶 2（ACE2）是 SARS-CoV 和 SARS-CoV-2 病毒的主要细胞进入受体。解整合素金属蛋白酶 17（ADAM17）是一种蛋白酶，可在细胞激活时将跨膜蛋白的细胞外结构域（包括 ACE2 和促炎细胞因子 TNF-α）从细胞表面切割下来。我们假设阻断 ADAM17 的活性会改变 COVID-19 的发病机制。为了评估这条途径，我们使用针对 ADAM17 的单克隆抗体 MEDI3622 在 K18-hACE2 转基因 COVID-19 小鼠模型中阻断了 ADAM17 的功能。与盐水处理的小鼠相比，用抗体治疗的小鼠更健康，濒死率更低，肺部病理明显减轻。然而，用 MEDI3622 治疗的小鼠肺部的病毒载量明显增加。因此，ADAM17 似乎具有关键的抗病毒作用，但也可能促进炎症损伤。由于炎症级联反应最终是 COVID-19 患者不良结局的原因，因此 MEDI3622 抗体可能有治疗应用。
