Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran; Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
Infect Genet Evol. 2021 Jun;90:104773. doi: 10.1016/j.meegid.2021.104773. Epub 2021 Feb 17.
The third pandemic of coronavirus infection, called COVID-19 disease, was first detected in November 2019th. Various determinants of disease progression such as age, sex, virus mutations, comorbidity, lifestyle, host immune response, and genetic background variation have caused clinical variability of COVID-19. The causative agent of COVID-19 is an enveloped coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that invades host cells using an endocytic pathway. The SARS-CoV-2 spike protein is the main viral protein that contributes to the fusion of the virus particle to the host cell through angiotensin-converting enzyme 2 (ACE2). The highly conserved expression of ACE2 is found in various animals, which indicates its pivotal physiological function. The ACE2 has a crucial role in vascular, renal, and myocardial physiology. Genetic factors contributing to the outcome of SARS-CoV-2 infection are unknown; however, variants in the specific sites of ACE2 gene could be regarded as a main genetic risk factor for COVID-19. Given that ACE2 is the main site for virus landing on host cells, the effect of amino acid sequences of ACE2 on host susceptibility to COVID-19 seems reasonable. It would likely have a substantial role in the occurrence of a wide range of clinical symptoms. Several ACE2 variants can affect the protein stability, influencing the interaction between spike protein and ACE2 through imposing conformational changes while some other variants are known to cause a decrease or an increase in the ligand-receptor affinity. The other variations are located at the proteolytic cleavage site, which can influence virus infection; because soluble ACE2 can act as a decoy receptor for virus and decrease virus intake by cell surface ACE2. Notably, polymorphisms of regulatory and non-coding regions such as promoter in ACE2, can play crucial role in different expression levels of ACE2 among different individuals. Many studies should be performed to investigate the involvement of ACE2 polymorphism with susceptibility to COVID-19. Herein, we discuss some reported associations between variants of ACE2 and COVID-19 in details. In addition, the mode of action of ACE2 and its role in SARS-CoV-2 infection are highlighted which is followed by addressing the effects of several ACE2 variants on its protein stability, viral tropism or ligand-receptor affinity, secondary and tertiary structure or protein conformation, proteolytic cleavage site, and finally inter-individual clinical variability in COVID-19. The polymorphisms of regulatory regions of ACE2 and their effect on expression levels of ACE2 are also provided in this review. Such studies can improve the prediction of the affinity of mutant ACE2 variations with spike protein, and help the biopharmaceutical industry to design effective approaches for recombinant hACE2 therapy and vaccination of COVID-19 disease.
新型冠状病毒感染的第三次大流行，即 COVID-19 疾病，于 2019 年 11 月首次被发现。疾病进展的各种决定因素，如年龄、性别、病毒突变、合并症、生活方式、宿主免疫反应和遗传背景的变化，导致了 COVID-19 的临床变异性。COVID-19 的病原体是一种包膜冠状病毒，称为严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2），它通过内吞途径入侵宿主细胞。SARS-CoV-2 的刺突蛋白是主要的病毒蛋白，通过血管紧张素转换酶 2（ACE2）促进病毒颗粒与宿主细胞的融合。ACE2 在各种动物中高度保守表达，表明其具有重要的生理功能。ACE2 在血管、肾脏和心肌生理学中起着至关重要的作用。导致 SARS-CoV-2 感染结果的遗传因素尚不清楚；然而，ACE2 基因特定部位的变异可能被视为 COVID-19 的主要遗传风险因素。鉴于 ACE2 是病毒降落在宿主细胞上的主要部位，ACE2 氨基酸序列对宿主易感性的影响似乎是合理的。它可能在广泛的临床症状发生中起重要作用。一些 ACE2 变异会影响蛋白质稳定性，通过引起构象变化来影响刺突蛋白与 ACE2 之间的相互作用，而其他一些变异则已知会降低或增加配体-受体的亲和力。其他变异位于蛋白水解切割位点，可影响病毒感染；因为可溶性 ACE2 可以作为病毒的诱饵受体，通过细胞表面 ACE2 减少病毒摄入。值得注意的是，ACE2 中的调节和非编码区域（如启动子）的多态性可在不同个体中 ACE2 的不同表达水平中发挥关键作用。需要进行许多研究来研究 ACE2 多态性与 COVID-19 易感性之间的关系。在此，我们详细讨论了 ACE2 变异与 COVID-19 之间的一些报道的相关性。此外，还强调了 ACE2 的作用机制及其在 SARS-CoV-2 感染中的作用，接着是解决几种 ACE2 变异对其蛋白稳定性、病毒嗜性或配体-受体亲和力、二级和三级结构或蛋白构象、蛋白水解切割位点以及最终 COVID-19 中个体间临床变异性的影响。本文还提供了 ACE2 调节区域的多态性及其对 ACE2 表达水平的影响。这些研究可以提高对突变 ACE2 变异与刺突蛋白亲和力的预测，帮助生物制药行业设计针对 COVID-19 疾病的有效方法，包括重组 hACE2 治疗和疫苗接种。
