The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice.
The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice.
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DOI：
10.7554/elife.70002
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发表时间：
2021-11-25
期刊：
影响因子：
7.7
通讯作者：
Skjoedt MO
中科院分区：
文献类型：
--
作者：
Bayarri-Olmos R;Johnsen LB;Idorn M;Reinert LS;Rosbjerg A;Vang S;Hansen CB;Helgstrand C;Bjelke JR;Bak-Thomsen T;Paludan SR;Garred P;Skjoedt MO
alpha/B.1.1.7 SARS-CoV-2谱系于2020年秋季在英国出现，并迅速传播到2021年冬季，当时它在许多欧洲国家造成了大多数新的COVID-19病例。发病率优势可能是由于受体结合域（RBD）残基变化（N501Y）驱动的适应度优势，该优势也独立出现在其他相关变异中，如β /B.1.351和γ /P。1株。在这里，我们展示了α /B.1.1.7变异的功能特征，并显示对人血管紧张素转换酶-2 （ACE-2）的亲和力增加了8倍。因此，与2020年初的SARS-CoV-2分离物相比，转基因hACE2小鼠在感染低剂量B.1.1.7后表现出更快的疾病进展和严重程度。当用恢复期个体的血清或抗RBD单克隆抗体激发时，N501Y变体显示出轻微但显著的逃避ACE-2/RBD抗体中和的潜力。这些数据表明，单天冬酰胺对酪氨酸取代的亲和力显著上升可能是B.1.1.7变异的高传播率和严重程度的原因。
The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.