SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury
Jasper Fuk-Woo Chan,
Hugo Yat-Hei Kwong,
Chris Chung-Sing Chan,
Vincent Kwok-Man Poon,
Chris Chun-Yiu Chan,
Kenn Ka-Heng Chik,
Kelvin Kai-Wang To,
David D Ho,
Lisa A Chakrabarti,
Posted 06 Oct 2021
bioRxiv DOI: 10.1101/2021.10.05.463282
Posted 06 Oct 2021
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.
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