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

Zhou, B.; Zhou, R.; Chan, J. F.-W.; Zeng, J.; Zhang, Q.; Yuan, S.; Liu, L.; Robinot, R.; Shan, S.; Ge, J.; Kwong, H. Y.-H.; Zhou, D.; Xu, H.; Chan, C. C.-S.; Poon, V. K.-M.; Chu, H.; Yue, M.; Kwan, K.-Y.; Chan, C.-Y.; Liu, N.; Chan, C. C.-Y.; Chik, K. K.-H.; Du, Z.; Au, K.-K.; Huang, H.; Man, H.-O.; Cao, J.; Li, C.; Wang, Z.; Zhou, J.; Song, Y.; Yeung, M.-L.; To, K. K.-W.; Ho, D. D.; Chakrabarti, L. A.; Wang, X.; Zhang, L.; Yuen, K.-Y.; Chen, Z.

doi:10.1101/2021.10.05.463282

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bioRxiv · 10.1101/2021.10.05.463282

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

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Abstract

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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Zhou, B., Zhou, R., Chan, J. F.-W., Zeng, J., Zhang, Q., Yuan, S., Liu, L., Robinot, R., Shan, S., Ge, J., Kwong, H. Y.-H., Zhou, D., Xu, H., Chan, C. C.-S., Poon, V. K.-M., Chu, H., Yue, M., Kwan, K.-Y., Chan, C.-Y., Liu, N., Chan, C. C.-Y., Chik, K. K.-H., Du, Z., Au, K.-K., Huang, H., Man, H.-O., Cao, J., Li, C., Wang, Z., Zhou, J., Song, Y., Yeung, M.-L., To, K. K.-W., Ho, D. D., Chakrabarti, L. A., Wang, X., Zhang, L., Yuen, K.-Y., Chen, Z.. 2021-10-06. SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury. https://doi.org/10.1101/2021.10.05.463282

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