Cross-neutralization of human and palm civet severe acute respiratory syndrome coronaviruses by antibodies targeting the receptor-binding domain of spike protein
Cross-neutralization of human and palm civet severe acute respiratory syndrome coronaviruses by antibodies targeting the receptor-binding domain of spike protein
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DOI：
10.4049/jimmunol.176.10.6085
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发表时间：
2006-05-15
影响因子：
4.4
通讯作者：
Jiang, Shibo
中科院分区：
文献类型：
--
作者：
He, Yuxian;Li, Jingjing;Jiang, Shibo
严重急性呼吸综合征冠状病毒（SARS CoV）刺突蛋白（S）被认为是疫苗设计的保护性抗原。我们以前证明，受体结合结构域（RBD）的S蛋白含有多个构象表位（Conf I-VI），赋予中和抗体的主要目标。在这里，我们表明，来自Tor 2，GD 03和SZ 3的S蛋白序列的重组RBD，人2002-2003和2003-2004 SARS冠状病毒和棕榈果子狸SARS冠状病毒的代表株，分别诱导免疫小鼠和兔的高滴度的交叉中和抗体对表达S蛋白的Tor 2，GD 03和SZ 3的假病毒。我们还证明了Tor 2-RBD诱导的Conf I-VI mAb可以有效地中和两种人SARS-CoV毒株Tor 2和GD 03。然而，只有Conf IV-VI，而不是Conf I-Ell mAb，中和果子狸SARS-CoV菌株SZ 3。所有这些mAb与三种RBD变体（Tor 2-RBD、GD 03-RBD）和SZ 3-RBD中的每一种显著反应，所述变体在几个氨基酸上不同。无论如何，通过RBD中保守残基的单点突变（例如，D429 A、R441 A或D454 A），并且Conf III表位受到E452 A或D463 A取代的显著影响。有趣的是，Conf V表位，这可能会重叠的受体结合基序，并诱导最有效的中和抗体，在这些突变体中是保守的。这些数据表明，SARS-CoV的主要中和表位在跨物种传播过程中明显保持不变，并且基于RBD的疫苗可能诱导针对人类和动物SARS-CoV变体的广泛保护。
The spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is considered as a protective Ag for vaccine design. We previously demonstrated that the receptor-binding domain (RBD) of S protein contains multiple conformational epitopes (Conf I-VI) that confer the major target of neutralizing Abs. Here we show that the recombinant RBDs derived from the S protein sequences of Tor2, GD03, and SZ3, the representative strains of human 2002-2003 and 2003-2004 SARS-CoV and palm civet SARS-CoV, respectively, induce in the immunized mice and rabbits high titers of cross-neutralizing Abs against pseudoviruses expressing S proteins of Tor2, GD03, and SZ3. We also demonstrate that the Tor2-RBD induced-Conf I-VI mAbs can potently neutralize both human SARS-CoV strains, Tor2 and GD03. However, only the Conf IV-VI, but not Conf I-Ell mAbs, neutralize civet SARS-CoV strain SZ3. All these mAbs reacted significantly with each of the three RBD variants (Tor2-RBD, GD03-RBD), and SZ3-RBD that differ at several amino acids. Regardless, the Conf I-IV and VI epitopes were completely disrupted by single-point mutation of the conserved residues in the RBD (e.g., D429A, R441A, or D454A) and the Conf III epitope was significantly affected by E452A or D463A substitution. Interestingly, the Conf V epitope, which may overlap the receptor-binding motif and induce most potent neutralizing Abs, was conserved in these mutants. These data suggest that the major neutralizing epitopes of SARS-CoV have been apparently maintained during cross-species transmission, and that RBD-based vaccines may induce broad protection against both human and animal SARS-CoV variants.