SARS-CoV-2 hijacks neutralizing dimeric IgA for nasal infection and injury in Syrian hamsters1

• Published in: Emerging microbes & infections Vol. 12; no. 2; p. 2245921
• Main Authors: Zhou, Biao, Zhou, Runhong, Jasper Fuk-Woo Chan, Zeng, Jianwei, Zhang, Qi, Yuan, Shuofeng, Liu, Li, Robinot, Rémy, Shan, Sisi, Liu, Na, Ge, Jiwan, Kwong, Hugo Yat-Hei, Zhou, Dongyan, Xu, Haoran, Chris Chung-Sing Chan, Poon, Vincent Kwok-Man, Chu, Hin, Yue, Ming, Ka-Yi, Kwan, Chun-Yin, Chan, Chris Chun-Yiu Chan, Kenn Ka-Heng Chik, Du, Zhenglong, Ka-Kit Au, Huang, Haode, Man, Hiu-On, Cao, Jianli, Li, Cun, Wang, Ziyi, Zhou, Jie, Song, Youqiang, Man-Lung Yeung, Kelvin Kai-Wang To, Ho, David D, Chakrabarti, Lisa A, Wang, Xinquan, Zhang, Linqi, Kwok-Yung, Yuen, Chen, Zhiwei
• Format: Journal Article
• Language: English
• Published: London Taylor & Francis Ltd 01.12.2023; Taylor & Francis; Taylor & Francis Group
• Subjects: antibody-mediated trans-infection; Coronaviruses; IgA; Infections; nasal turbinate; neutralizing antibody; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2
• ISSN: 2222-1751; 2222-1751
• DOI: 10.1080/22221751.2023.2245921

Prevention of robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) requires in vivo 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.