TY - JOUR T1 - SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury JF - bioRxiv DO - 10.1101/2021.10.05.463282 SP - 2021.10.05.463282 AU - Biao Zhou AU - Runhong Zhou AU - Jasper Fuk-Woo Chan AU - Jianwei Zeng AU - Qi Zhang AU - Shuofeng Yuan AU - Li Liu AU - Rémy Robinot AU - Sisi Shan AU - Jiwan Ge AU - Hugo Yat-Hei Kwong AU - Dongyan Zhou AU - Haoran Xu AU - Chris Chung-Sing Chan AU - Vincent Kwok-Man Poon AU - Hin Chu AU - Ming Yue AU - Ka-Yi Kwan AU - Chun-Yin Chan AU - Na Liu AU - Chris Chun-Yiu Chan AU - Kenn Ka-Heng Chik AU - Zhenglong Du AU - Ka-Kit Au AU - Haode Huang AU - Hiu-On Man AU - Jianli Cao AU - Cun Li AU - Ziyi Wang AU - Jie Zhou AU - Youqiang Song AU - Man-Lung Yeung AU - Kelvin Kai-Wang To AU - David D. Ho AU - Lisa A. Chakrabarti AU - Xinquan Wang AU - Linqi Zhang AU - Kwok-Yung Yuen AU - Zhiwei Chen Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/06/2021.10.05.463282.abstract N2 - 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.Competing Interest StatementJ.F.W.C. has received travel grants from Pfizer Corporation Hong Kong and Astellas Pharma Hong Kong Corporation Limited and was an invited speaker for Gilead Sciences Hong Kong Limited and Luminex Corporation. The funding sources had no role in study design, data collection, analysis or interpretation or writing of the report. The other authors declare no conflicts of interest except for a provisional patent application filed for human monoclonal antibodies generated in our laboratory. ER -