From National Heart and Lung Institute, Imperial College London, London, UK.
Respiratory Medicine, Imperial College Healthcare NHS Trust, London, UK.
QJM. 2023 Sep 12;116(8):629-634. doi: 10.1093/qjmed/hcaa241.
Coronavirus disease 2019 (COVID-19) has presented physicians with an unprecedented number of challenges and mortality. The basic question is why, in contrast to other 'respiratory' viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in such multi-systemic, life-threatening complications and a severe pulmonary vasculopathy. It is widely known that SARS-CoV-2 uses membrane-bound angiotensin-converting enzyme 2 (ACE2) as a receptor, resulting in internalization of the complex by the host cell. We discuss the evidence that failure to suppress coronaviral replication within 5 days results in sustained downregulation of ACE2 protein expression and that ACE2 is under negative-feedback regulation. We then expose openly available experimental repository data that demonstrate the gene for ACE2 lies in a novel cluster of inter-regulated genes on the X chromosome including PIR encoding pirin (quercetin 2,3-dioxygenase), and VEGFD encoding the predominantly lung-expressed vascular endothelial growth factor D. The five double-elite enhancer/promoters pairs that are known to be operational, and shared read-through lncRNA transcripts, imply that ongoing SARS-CoV-2 infection will reduce host defences to reactive oxygen species, directly generate superoxide O2·- and H2O2 (a ' ROS storm'), and impair pulmonary endothelial homeostasis. Published cellular responses to oxidative stress complete the loop to pathophysiology observed in severe COVID-19. Thus, for patients who fail to rapidly suppress viral replication, the newly appreciated ACE2 co-regulated gene cluster predicts delayed responses that would account for catastrophic deteriorations. We conclude that ACE2 homeostatic drives provide a unified understanding that should help optimize therapeutic approaches during the wait until safe, effective vaccines and antiviral therapies for SARS-CoV-2 are delivered.
新型冠状病毒病 2019（COVID-19）给医生带来了前所未有的挑战和死亡率。基本问题是，与其他“呼吸道”病毒相比，为什么严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染会导致如此多系统的、危及生命的并发症和严重的肺血管病变。众所周知，SARS-CoV-2 使用膜结合的血管紧张素转换酶 2（ACE2）作为受体，导致宿主细胞内化该复合物。我们讨论了未能在 5 天内抑制冠状病毒复制会导致 ACE2 蛋白表达持续下调的证据，并且 ACE2 受到负反馈调节。然后，我们公开了可用的实验存储库数据，这些数据表明 ACE2 的基因位于 X 染色体上一个新的相互调节基因簇中，包括编码吡啉（槲皮素 2,3-双加氧酶）的 PIR 和编码主要在肺部表达的血管内皮生长因子 D 的 VEGFD。已知有五个双精英增强子/启动子对在起作用，并且具有共享的通读长非编码 RNA 转录本，这意味着持续的 SARS-CoV-2 感染将降低宿主对活性氧的防御能力，直接产生超氧化物 O2·-和 H2O2（“ROS 风暴”），并损害肺内皮细胞的稳态。已发表的细胞对氧化应激的反应完成了严重 COVID-19 中观察到的病理生理学循环。因此，对于未能迅速抑制病毒复制的患者，新出现的 ACE2 共同调节基因簇预测会出现延迟反应，这将导致灾难性恶化。我们得出结论，ACE2 稳态驱动提供了一个统一的理解，这应该有助于在等待安全有效的 SARS-CoV-2 疫苗和抗病毒疗法的同时优化治疗方法。
