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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies
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Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies

机译：人类单克隆抗体对SARS冠状病毒分离株的强效交叉反应中和

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摘要

The severe acute respiratory syndrome coronavirus (SARS-CoV) caused a worldwide epidemic in late 2002/early 2003 and a second outbreak in the winter of 2003/2004 by an independent animal-to-human transmission. The GD03 strain, which was isolated from an index patient of the second outbreak, was reported to resist neutralization by the human monoclonal antibodies (hmAbs) 80R and S3.1, which can potently neutralize isolates from the first outbreak. Here we report that two hmAbs, m396 and S230.15, potently neutralized GD03 and representative isolates from the first SARS outbreak (Urbani, Tor2) and from palm civets (SZ3, SZ16). These antibodies also protected mice challenged with the Urbani or recombinant viruses bearing the GD03 and SZ16 spike (S) glycoproteins. rnBoth antibodies competed with the SARS-CoV receptor, ACE2, for binding to the receptor-binding domain (RBD), suggesting a mechanism of neutralization that involves interference with the SARS-CoV-ACE2 interaction. Two putative hot-spot residues in the RBD (Ile-489 and Tyr-491) were identified within the SARS-CoV spike that likely contribute to most of the m396-binding energy. Residues Ile-489 and Tyr-491 are highly conserved within the SARS-CoV spike, indicating a possible mechanism of the m396 cross-reactivity. Sequence analysis and mutagenesis data show that m396 might neutralize all zoonotic and epidemic SARS-CoV isolates with known sequences, except strains derived from bats. These antibodies exhibit cross-reactivity against isolates from the two SARS outbreaks and palm civets and could have potential applications for diagnosis, prophylaxis, and treatment of SARS-CoV infections.
机译：严重的急性呼吸系统综合症冠状病毒（SARS-CoV）在2002年底/ 2003年初引起了世界范围的流行，并在2003/2004年冬季通过独立的人对人的传播再次爆发。 GD03菌株是从第二次暴发的索引患者中分离出来的，据报道它能抵抗人单克隆抗体（hmAbs）80R和S3.1的中和作用，它们可以有效地中和第一次暴发的分离株。在这里，我们报道了两个hmAb，即m396和S230.15，有效地中和了GD03和来自首次SARS爆发（Urbani，Tor2）和棕榈科动物（SZ3，SZ16）的代表性分离株。这些抗体还保护了受Urbani或带有GD03和SZ16突突（S）糖蛋白的重组病毒攻击的小鼠。两种抗体都与SARS-CoV受体ACE2竞争与受体结合域（RBD）的结合，这表明中和机制涉及干扰SARS-CoV-ACE2相互作用。在SARS-CoV尖峰中发现了RBD中两个假定的热点残基（Ile-489和Tyr-491），这可能与大多数m396结合能有关。残基Ile-489和Tyr-491在SARS-CoV峰值内高度保守，表明m396交叉反应的可能机制。序列分析和诱变数据表明，m396可能会中和所有具有已知序列的人畜共患病和流行性SARS-CoV分离株，但蝙蝠衍生的菌株除外。这些抗体对来自两次SARS暴发和棕榈叶的分离株表现出交叉反应性，并且在诊断，预防和治疗SARS-CoV感染方面可能具有潜在的应用。

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