AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (SAR), People's Republic of China.
Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (SAR), People's Republic of China.
Emerg Microbes Infect. 2023 Dec;12(2):2245921. doi: 10.1080/22221751.2023.2245921.
Prevention of robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) requires evaluation of IgA neutralizing antibodies. Here, we report the efficacy of receptor binding domain (RBD)-specific monomeric B8-mIgA1 and B8-mIgA2, and dimeric B8-dIgA1, B8-dIgA2 and TH335-dIgA1 against intranasal SARS-CoV-2 challenge in Syrian hamsters. These antibodies exhibited comparable neutralization potency against authentic virus by competing with human angiotensin converting enzyme-2 (ACE2) receptor for RBD binding. While reducing viral loads in lungs significantly, prophylactic intranasal B8-dIgA unexpectedly led to high amount of infectious viruses and extended damage in NT compared to controls. Mechanistically, B8-dIgA failed to inhibit SARS-CoV-2 cell-to-cell transmission, but was hijacked by the virus through dendritic cell-mediated trans-infection of NT epithelia leading to robust nasal infection. Cryo-EM further revealed B8 as a class II antibody binding trimeric RBDs in 3-up or 2-up/1-down conformation. Neutralizing dIgA, therefore, may engage an unexpected mode of SARS-CoV-2 nasal infection and injury.
预防鼻腔内强烈的严重急性呼吸系统综合征冠状病毒 2 型（SARS-CoV-2）感染需要评估 IgA 中和抗体。在这里，我们报告了受体结合域（RBD）特异性单体 B8-mIgA1 和 B8-mIgA2，以及二聚体 B8-dIgA1、B8-dIgA2 和 TH335-dIgA1 对叙利亚仓鼠鼻内 SARS-CoV-2 挑战的功效。这些抗体通过与人类血管紧张素转换酶 2（ACE2）受体竞争 RBD 结合，对真实病毒具有相当的中和效力。虽然预防性鼻腔内 B8-dIgA 显著降低了肺部的病毒载量，但与对照组相比，它出人意料地导致了鼻腔内大量传染性病毒和 NT 损伤的延长。从机制上讲，B8-dIgA 未能抑制 SARS-CoV-2 的细胞间传播，但通过树突状细胞介导的 NT 上皮的转染，被病毒劫持，导致强烈的鼻感染。冷冻电镜进一步显示 B8 以 3 向上或 2 向上/1 向下构象结合三聚体 RBD 作为 II 类抗体。因此，中和性 dIgA 可能采用了 SARS-CoV-2 鼻感染和损伤的意外模式。
