Susceptibilities of Human ACE2 Genetic Variants in Coronavirus Infection.
Susceptibilities of Human ACE2 Genetic Variants in Coronavirus Infection.
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DOI：
10.1128/jvi.01492-21
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发表时间：
2022-01-12
影响因子：
5.4
通讯作者：
Ding Q
中科院分区：
文献类型：
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作者：
Ren W;Zhu Y;Lan J;Chen H;Wang Y;Shi H;Feng F;Chen DY;Close B;Zhao X;Wu J;Tian B;Yuan Z;Zhou D;Saeed M;Wang X;Zhang R;Ding Q
2019冠状病毒病（COVID-19）大流行由严重急性呼吸系统综合征冠状病毒2型（SARS-CoV-2）引起，已导致全球超过2. 35亿例病例和480万例死亡（2021年10月），各地区╱种族的发病率和死亡率各不相同。冠状病毒SARS-CoV、SARS-CoV-2和HCoV-NL 63利用血管紧张素转换酶2（ACE 2）作为受体进入细胞。我们假设ACE 2的遗传变异性可能导致COVID-19的临床结局可变。为了验证这一假设，我们首先对ACE 2编码区的单核苷酸多态性（SNP）进行了计算机模拟研究。然后，我们应用遗传学，生物化学和病毒学的综合方法来探索选择ACE 2变体结合冠状病毒刺突蛋白和介导病毒进入的能力。我们鉴定了ACE 2 D355 N变体，其限制了刺突蛋白-ACE 2相互作用，从而限制了体外和体内感染。总之，ACE 2多态性可以调节SARS-CoV-2的易感性，这可能导致不同的疾病严重程度。重要性感染SARS-CoV-2（引起COVID-19的病毒）的患者之间的疾病严重程度存在相当大的差异。人类遗传变异可以影响疾病的结果，冠状病毒SARS-CoV，SARS-CoV-2和HCoV-NL 63利用人类ACE 2作为受体进入细胞。我们发现几个错义ACE 2单核苷酸变体（SNV）与SARS-CoV，SARS-CoV-2和NL 63-HCoV的刺突蛋白的结合显着改变。我们鉴定了ACE 2 SNP D355 N，其限制了刺突蛋白-ACE 2相互作用，因此具有保护个体免受SARS-CoV-2感染的潜力。我们的研究强调ACE 2多态性可能影响人类对SARS-CoV-2的易感性，这可能有助于SARS-CoV-2传播和致病性的种族和地理差异。
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 235 million cases worldwide and 4.8 million deaths (October 2021), with various incidences and mortalities among regions/ethnicities. The coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize the angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells. We hypothesized that the genetic variability in ACE2 may contribute to the variable clinical outcomes of COVID-19. To test this hypothesis, we first conducted an in silico investigation of single-nucleotide polymorphisms (SNPs) in the coding region of ACE2. We then applied an integrated approach of genetics, biochemistry, and virology to explore the capacity of select ACE2 variants to bind coronavirus spike proteins and mediate viral entry. We identified the ACE2 D355N variant that restricts the spike protein-ACE2 interaction and consequently limits infection both in vitro and in vivo. In conclusion, ACE2 polymorphisms could modulate susceptibility to SARS-CoV-2, which may lead to variable disease severity. IMPORTANCE There is considerable variation in disease severity among patients infected with SARS-CoV-2, the virus that causes COVID-19. Human genetic variation can affect disease outcome, and the coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize human ACE2 as the receptor to enter cells. We found that several missense ACE2 single-nucleotide variants (SNVs) that showed significantly altered binding with the spike proteins of SARS-CoV, SARS-CoV-2, and NL63-HCoV. We identified an ACE2 SNP, D355N, that restricts the spike protein-ACE2 interaction and consequently has the potential to protect individuals against SARS-CoV-2 infection. Our study highlights that ACE2 polymorphisms could impact human susceptibility to SARS-CoV-2, which may contribute to ethnic and geographical differences in SARS-CoV-2 spread and pathogenicity.