SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury

Zhou, Biao; Zhou, Runhong; Chan, Jasper Fuk-Woo; Zeng, Jianwei; Zhang, Qi; Yuan, Shuofeng; Liu, Li; Robinot, Rémy; Shan, Sisi; Ge, Jiwan; Kwong, Hugo Yat-Hei; Zhou, Dongyan; Xu, Haoran; Chan, Chris Chung-Sing; Poon, Vincent Kwok-Man; Chu, Hin; Yue, Ming; Kwan, Ka-Yi; Chan, Chun-Yin; Liu, Na; Chan, Chris Chun-Yiu; Chik, Kenn Ka-Heng; Du, Zhenglong; Au, Ka-Kit; Huang, Haode; Man, Hiu-On; Cao, Jianli; Li, Cun; Wang, Ziyi; Zhou, Jie; Song, Youqiang; Yeung, Man-Lung; To, Kelvin Kai-Wang; Ho, David D.; Chakrabarti, Lisa A.; Wang, Xinquan; Zhang, Linqi; Yuen, Kwok-Yung; Chen, Zhiwei

Robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) accounts for high viral transmissibility, yet whether neutralizing IgA antibodies can control it remains unknown. Here, we evaluated receptor binding domain (RBD)-specific monomeric B8-mIgA1 and B8-mIgA2, and dimeric B8-dIgA1 and B8-dIgA2 against intranasal SARS-CoV-2 challenge in Syrian hamsters. These antibodies exhibited comparably potent neutralization against authentic virus by competing with human angiotensin converting enzyme-2 (ACE2) receptor for RBD binding. While reducing viruses in lungs, pre-exposure intranasal B8-dIgA1 or B8-dIgA2 led to 81-fold more infectious viruses and severer damage in NT than placebo. Virus-bound B8-dIgA1 and B8-dIgA2 could engage CD209 as an alternative receptor for entry into ACE2-negative cells and allowed viral cell-to-cell transmission. Cryo-EM revealed B8 as a class II neutralizing antibody binding trimeric RBDs in 3-up or 2-up/1-down conformation. Therefore, RBD-specific neutralizing dIgA engages an unexpected action for enhanced SARS-CoV-2 nasal infection and injury in Syrian hamsters.