Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS Pathog. 2024 Sep 5;20(9):e1012493. doi: 10.1371/journal.ppat.1012493. eCollection 2024 Sep.
Grasping the roles of epitopes in viral glycoproteins is essential for unraveling the structure and function of these proteins. Up to now, all identified epitopes have been found to either neutralize, have no effect on, or enhance viral entry into cells. Here, we used nanobodies (single-domain antibodies) as probes to investigate a unique epitope on the SARS-CoV-2 spike protein, located outside the protein's receptor-binding domain. Nanobody binding to this epitope enhances the cell entry of prototypic SARS-CoV-2, while neutralizing the cell entry of SARS-CoV-2 Omicron variant. Moreover, nanobody binding to this epitope promotes both receptor binding activity and post-attachment activity of prototypic spike, explaining the enhanced viral entry. The opposite occurs with Omicron spike, explaining the neutralized viral entry. This study reveals a unique epitope that can both enhance and neutralize viral entry across distinct viral variants, suggesting that epitopes may vary their roles depending on the viral context. Consequently, antibody therapies should be assessed across different viral variants to confirm their efficacy and safety.
解析病毒糖蛋白中表位的作用对于揭示这些蛋白的结构和功能至关重要。到目前为止，所有已鉴定的表位要么具有中和作用，要么对病毒进入细胞没有影响，要么增强病毒进入细胞的能力。在这里，我们使用纳米抗体（单域抗体）作为探针来研究 SARS-CoV-2 刺突蛋白上一个独特的表位，该表位位于蛋白的受体结合域之外。纳米抗体与该表位的结合增强了原型 SARS-CoV-2 的细胞进入，同时中和了 SARS-CoV-2 奥密克戎变体的细胞进入。此外，纳米抗体与该表位的结合促进了原型刺突的受体结合活性和附着后活性，解释了增强的病毒进入。奥密克戎刺突则相反，解释了被中和的病毒进入。这项研究揭示了一个独特的表位，它可以增强和中和不同病毒变体的病毒进入，这表明表位可能根据病毒的情况改变其作用。因此，应该在不同的病毒变体中评估抗体疗法，以确认其疗效和安全性。
