Conformational flexibility in neutralization of SARS-CoV-2 by naturally elicited anti-SARS-CoV-2 antibodies.
Conformational flexibility in neutralization of SARS-CoV-2 by naturally elicited anti-SARS-CoV-2 antibodies.
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DOI：
10.1038/s42003-022-03739-5
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发表时间：
2022-08-05
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
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作者：
随着SARS-CoV-2新变种的不断出现，评估在野生型SARS-CoV-2感染过程中自然产生的抗体的交叉中和能力是重要的。在本研究中，我们评价了先前从感染武汉-HU-1毒株的恢复期供体中分离的9种抗SARS-CoV-2单抗(MAbs)对SARS-CoV-2关注变种(VOC)Alpha、Beta、Gamma、Delta和Omicron的活性。通过检测一系列突变的刺突受体结合域(RBD)蛋白、细胞表达的VOCs的刺突蛋白，以及中和SARS-CoV-2 VOCs作为假病毒或作为培养中的正宗病毒，我们发现针对ACE2结合位点(ACE2bs)的单抗比抗RBD的非ACE2bs单抗对病毒进化更敏感，其中两种单抗保持了对所有测试VOC的效力。在本研究的第二部分，我们通过结构表征揭示了两株抗SARS-CoV-2中和单抗在高分子分辨率下的中和机理。我们用SARS-CoV-2尖峰三聚体和RbD分别在4.5 ä和2.42RbD的分辨率下求解了Delta-中和ACE2bs单抗TAU-2303的结构，揭示了与RbD和ACE2之间类似的结合模式。此外，我们还提供了与SARS-CoV-2尖峰三聚体复合的第二抗体TAU-2212的五个额外结构(分辨率为4.7 ä、7.3 ä、6.4 ä、3.3 ä和6.1 ä)。Tau-2212只与一个四元表位结合，并表现出一种独特的、灵活的中和模式，涉及到五种不同构象之间的转换，抗体的两个臂被招募用于交联尖峰内和尖峰间的RBD亚基。我们的研究为抗体如何中和SARS-CoV-2及其新出现的变种提供了更多的机制理解，并对再次感染的可能性提供了见解。本文报道了从感染武汉-HU-1毒株的恢复期献血者中分离的9株单抗对SARS-CoV-2及其变异体的中和作用，以及其中两株单抗与RBD和SPAKE结合的结构特征。
As new variants of SARS-CoV-2 continue to emerge, it is important to assess the cross-neutralizing capabilities of antibodies naturally elicited during wild type SARS-CoV-2 infection. In the present study, we evaluate the activity of nine anti-SARS-CoV-2 monoclonal antibodies (mAbs), previously isolated from convalescent donors infected with the Wuhan-Hu-1 strain, against the SARS-CoV-2 variants of concern (VOC) Alpha, Beta, Gamma, Delta and Omicron. By testing an array of mutated spike receptor binding domain (RBD) proteins, cell-expressed spike proteins from VOCs, and neutralization of SARS-CoV-2 VOCs as pseudoviruses, or as the authentic viruses in culture, we show that mAbs directed against the ACE2 binding site (ACE2bs) are more sensitive to viral evolution compared to anti-RBD non-ACE2bs mAbs, two of which retain their potency against all VOCs tested. At the second part of our study, we reveal the neutralization mechanisms at high molecular resolution of two anti-SARS-CoV-2 neutralizing mAbs by structural characterization. We solve the structures of the Delta-neutralizing ACE2bs mAb TAU-2303 with the SARS-CoV-2 spike trimer and RBD at 4.5 Å and 2.42 Å resolutions, respectively, revealing a similar mode of binding to that between the RBD and ACE2. Furthermore, we provide five additional structures (at resolutions of 4.7 Å, 7.3 Å, 6.4 Å, 3.3 Å, and 6.1 Å) of a second antibody, TAU-2212, complexed with the SARS-CoV-2 spike trimer. TAU-2212 binds an exclusively quaternary epitope, and exhibits a unique, flexible mode of neutralization that involves transitioning between five different conformations, with both arms of the antibody recruited for cross linking intra- and inter-spike RBD subunits. Our study provides additional mechanistic understanding about how antibodies neutralize SARS-CoV-2 and its emerging variants and provides insights on the likelihood of reinfections. The neutralization of SARS-CoV-2 and variants of concern by nine monoclonal antibodies (mAb) isolated from convalescent donors infected with the Wuhan-Hu-1 strain alongside structural characterization of two of the mAbs in complex with the RBD and spike are presented.
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影响因子：
16.6
作者：
Greaney AJ;Starr TN;Barnes CO;Weisblum Y;Schmidt F;Caskey M;Gaebler C;Cho A;Agudelo M;Finkin S;Wang Z;Poston D;Muecksch F;Hatziioannou T;Bieniasz PD;Robbiani DF;Nussenzweig MC;Bjorkman PJ;Bloom JD
通讯作者：
Bloom JD
DOI：
10.1056/nejmoa2029849
发表时间：
2021-01-21
期刊：
The New England journal of medicine
影响因子：
--
作者：
Chen P;Nirula A;Heller B;Gottlieb RL;Boscia J;Morris J;Huhn G;Cardona J;Mocherla B;Stosor V;Shawa I;Adams AC;Van Naarden J;Custer KL;Shen L;Durante M;Oakley G;Schade AE;Sabo J;Patel DR;Klekotka P;Skovronsky DM;BLAZE-1 Investigators
通讯作者：
BLAZE-1 Investigators
影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ
SARS-COV-2血统的估计可传播和影响B.1.1.7在英国。
DOI：
10.1126/science.abg3055
发表时间：
2021-04-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Davies NG;Abbott S;Barnard RC;Jarvis CI;Kucharski AJ;Munday JD;Pearson CAB;Russell TW;Tully DC;Washburne AD;Wenseleers T;Gimma A;Waites W;Wong KLM;van Zandvoort K;Silverman JD;CMMID COVID-19 Working Group;COVID-19 Genomics UK (COG-UK) Consortium;Diaz-Ordaz K;Keogh R;Eggo RM;Funk S;Jit M;Atkins KE;Edmunds WJ
通讯作者：
Edmunds WJ
影响因子：
64.5
作者：
Hoffmann M;Arora P;Groß R;Seidel A;Hörnich BF;Hahn AS;Krüger N;Graichen L;Hofmann-Winkler H;Kempf A;Winkler MS;Schulz S;Jäck HM;Jahrsdörfer B;Schrezenmeier H;Müller M;Kleger A;Münch J;Pöhlmann S
通讯作者：
Pöhlmann S