Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains.
Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains.
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DOI：
10.1371/journal.ppat.1010951
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发表时间：
2022-11
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
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SARS-CoV-2继续获得刺突受体结合结构域（RBD）中的突变，这些突变影响ACE 2受体结合、折叠稳定性和抗体识别。深度突变扫描前瞻性地表征突变对这些生化特性的影响，从而能够快速评估病毒监测期间发现的新突变。然而，突变的影响可能会随着病毒的进化而改变，需要更新深度突变扫描。我们确定了Omicron BA.1和BA.2 RBD中所有单个氨基酸突变对ACE 2结合亲和力、RBD折叠和LY-CoV 1404（bebtelovimab）单克隆抗体结合逃逸的影响。Omicron RBD中某些突变的影响不同于在祖先武汉-胡-1背景中测量的那些。这些上位性变化很大程度上类似于先前在α变体中观察到的那些，这是由于收敛上位性修饰N501 Y置换。然而，Omicron变异体显示出额外的谱系特异性变化，包括导致Omicron中存在的Q498 R和N501 Y取代在该背景下比早期病毒株更有利的上位性现象的例子。相比之下，Omicron取代Q493 R没有表现出巩固的迹象，与衍生状态，R493，是不利的ACE 2结合在Omicron RBD在武汉-胡-1。可能由于这个原因，在Omicron亚变体（包括BA.4/BA.5和BA.2.75）中发生了R493 Q回复突变，其中来自R493 Q回复突变的亲和缓冲液可能会增强并发抗原变化。与先前的研究一致，我们发现Omicron RBD的表达减少，并确定了改善这种缺陷的候选稳定突变。最后，我们的图谱突出显示，与祖先武汉-胡-1背景相比，BA.1和BA.2中逃避LY-CoV 1404抗体结合的位点扩大。这些BA.1和BA.2深度突变扫描数据集识别了RBD突变格局的变化，并为病毒监测的持续努力提供了信息。SARS-CoV-2的进化部分是通过其刺突受体结合域的突变实现的。随着这些突变在进化的变体中积累，它们通过上位性现象塑造了病毒未来的进化潜力。我们表征了Omicron BA.1和BA.2受体结合结构域突变对ACE 2受体结合、蛋白质折叠和临床LY-CoV 1404抗体识别的功能影响。然后，我们将测量结果与早期变体的先前数据进行了比较。这些比较确定了可能改变Omicron进化未来模式的上位性模式，例如特定亲和力增强突变可用性的转换以及用于COVID-19治疗性治疗的关键单克隆抗体的抗体逃逸路径数量的扩大。这项工作为病毒监测和预测方面的持续努力提供了信息。
SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes the impacts of mutations on these biochemical properties, enabling rapid assessment of new mutations seen during viral surveillance. However, the effects of mutations can change as the virus evolves, requiring updated deep mutational scans. We determined the impacts of all single amino acid mutations in the Omicron BA.1 and BA.2 RBDs on ACE2-binding affinity, RBD folding, and escape from binding by the LY-CoV1404 (bebtelovimab) monoclonal antibody. The effects of some mutations in Omicron RBDs differ from those measured in the ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble those previously seen in the Alpha variant due to the convergent epistatically modifying N501Y substitution. However, Omicron variants show additional lineage-specific shifts, including examples of the epistatic phenomenon of entrenchment that causes the Q498R and N501Y substitutions present in Omicron to be more favorable in that background than in earlier viral strains. In contrast, the Omicron substitution Q493R exhibits no sign of entrenchment, with the derived state, R493, being as unfavorable for ACE2 binding in Omicron RBDs as in Wuhan-Hu-1. Likely for this reason, the R493Q reversion has occurred in Omicron sub-variants including BA.4/BA.5 and BA.2.75, where the affinity buffer from R493Q reversion may potentiate concurrent antigenic change. Consistent with prior studies, we find that Omicron RBDs have reduced expression, and identify candidate stabilizing mutations that ameliorate this deficit. Last, our maps highlight a broadening of the sites of escape from LY-CoV1404 antibody binding in BA.1 and BA.2 compared to the ancestral Wuhan-Hu-1 background. These BA.1 and BA.2 deep mutational scanning datasets identify shifts in the RBD mutational landscape and inform ongoing efforts in viral surveillance. SARS-CoV-2 evolves in part through mutations in its spike receptor-binding domain. As these mutations accumulate in evolved variants, they shape the future evolutionary potential of the virus through the phenomenon of epistasis. We characterized the functional impacts of mutations in the Omicron BA.1 and BA.2 receptor-binding domains on ACE2 receptor binding, protein folding, and recognition by the clinical LY-CoV1404 antibody. We then compared the measurements to prior data for earlier variants. These comparisons identify patterns of epistasis that may alter future patterns of Omicron evolution, such as turnover in the availability of specific affinity-enhancing mutations and an expansion in the number of paths of antibody escape from a key monoclonal antibody used for therapeutic treatment of COVID-19. This work informs continued efforts in viral surveillance and forecasting.
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DOI：
10.1126/science.abq0203
发表时间：
2022-08-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.9
作者：
McCallum, Matthew;Czudnochowski, Nadine;Rosen, Laura E.;Zepeda, Samantha K.;Bowen, John E.;Walls, Alexandra C.;Hauser, Kevin;Joshi, Anshu;Stewart, Cameron;Dillen, Josh R.;Powell, Abigail E.;Croll, Tristan, I;Nix, Jay;Virgin, Herbert W.;Corti, Davide;Snell, Gyorgy;Veesler, David
通讯作者：
Veesler, David
影响因子：
64.8
作者：
Cao, Yunlong;Yisimayi, Ayijiang;Jian, Fanchong;Song, Weiliang;Xiao, Tianhe;Wang, Lei;Du, Shuo;Wang, Jing;Li, Qianqian;Chen, Xiaosu;Yu, Yuanling;Wang, Peng;Zhang, Zhiying;Liu, Pulan;An, Ran;Hao, Xiaohua;Wang, Yao;Feng, Rui;Sun, Haiyan;Zhao, Lijuan;Zhang, Wen;Zhao, Dong;Zheng, Jiang;Yu, Lingling;Li, Can;Zhang, Na;Wang, Rui;Niu, Xiao;Yang, Sijie;Song, Xuetao;Chai, Yangyang;Hu, Ye;Shi, Yansong;Zheng, Linlin;Li, Zhiqiang;Gu, Qingqing;Shao, Fei;Huang, Weijin;Jin, Ronghua;Shen, Zhongyang;Wang, Youchun;Wang, Xiangxi;Xiao, Junyu;Xie, Xiaoliang Sunney
通讯作者：
Xie, Xiaoliang Sunney
影响因子：
30.3
作者：
Javanmardi, Kamyab;Segall-Shapiro, Thomas H.;Chou, Chia-Wei;Boutz, Daniel R.;Olsen, Randall J.;Xie, Xuping;Xia, Hongjie;Shi, Pei-Yong;Johnson, Charlie D.;Annapareddy, Ankur;Weaver, Scott;Musser, James M.;Ellington, Andrew D.;Finkelstein, Ilya J.;Gollihar, Jimmy D.
通讯作者：
Gollihar, Jimmy D.
影响因子：
6.7
作者：
Greaney AJ;Starr TN;Eguia RT;Loes AN;Khan K;Karim F;Cele S;Bowen JE;Logue JK;Corti D;Veesler D;Chu HY;Sigal A;Bloom JD
通讯作者：
Bloom JD