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

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

doi:10.1080/22221751.2023.2245921

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

Emerg Microbes Infect. 2023 Dec;12(2):2245921. doi: 10.1080/22221751.2023.2245921.

Authors

Biao Zhou^{1

2}, Runhong Zhou^{1

2

3}, Jasper Fuk-Woo Chan^{2

3

4

5

6}, Jianwei Zeng⁷, Qi Zhang⁸, Shuofeng Yuan^{2

3

4

5}, Li Liu^{1

2

3}, Rémy Robinot⁹, Sisi Shan⁸, Na Liu^{1

5}, Jiwan Ge⁷, Hugo Yat-Hei Kwong¹, Dongyan Zhou^{1

2}, Haoran Xu^{1

2}, Chris Chung-Sing Chan², Vincent Kwok-Man Poon², Hin Chu^{2

3

4

5}, Ming Yue¹⁰, Ka-Yi Kwan¹, Chun-Yin Chan¹, Chris Chun-Yiu Chan², Kenn Ka-Heng Chik², Zhenglong Du¹, Ka-Kit Au¹, Haode Huang¹, Hiu-On Man¹, Jianli Cao², Cun Li², Ziyi Wang⁷, Jie Zhou^{2

3

4

5}, Youqiang Song¹⁰, Man-Lung Yeung^{2

3

4

5}, Kelvin Kai-Wang To^{2

3

4

5}, David D Ho¹¹, Lisa A Chakrabarti⁹, Xinquan Wang⁷, Linqi Zhang⁸, Kwok-Yung Yuen^{2

3

4

5

6}, Zhiwei Chen^{1

2

3

4

5}

Affiliations

¹ AIDS Institute, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (SAR), People's Republic of China.
² Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (SAR), People's Republic of China.
³ Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Pak Shek Kok, Hong Kong Special Administrative Region (SAR), People's Republic of China.
⁴ State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (SAR), People's Republic of China.
⁵ Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People's Republic of China.
⁶ Hainan-Medical University - The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, and Academician Workstation of Hainan Province, Hainan Medical University, Haikou, People's Republic of China, and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (SAR), People's Republic of China.
⁷ The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing, People's Republic of China.
⁸ NexVac Research Center, Comprehensive AIDS Research Center, Center for Infectious Diseases, School of Medicine, Tsinghua University, Beijing, People's Republic of China.
⁹ Control of Chronic Viral Infections Group, Virus & Immunity Unit, Institute Pasteur, Paris, France; CNRS UMR, Paris, France.
¹⁰ School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (SAR), People's Republic of China.
¹¹ Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Abstract

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.

Keywords: IgA; SARS-CoV-2; antibody-mediated trans-infection; nasal turbinate; neutralizing antibody.

MeSH terms

Animals
Antibodies, Neutralizing
Antibodies, Viral
COVID-19*
Common Cold*
Cricetinae
Humans
Immunoglobulin A
Mesocricetus
SARS-CoV-2
Spike Glycoprotein, Coronavirus

Substances

Antibodies, Viral
Antibodies, Neutralizing
Immunoglobulin A
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Grants and funding

We acknowledge financial supports from the Hong Kong Research Grants Council Collaborative Research Fund (C7156-20GF, C1134-20GF and C7042-21GF); the National Key Research and Development Project of China (2020YFC0860600) and the National Program on Key Research Project of China (2020YFC0860600, 2020YFA0707500, 2020YFA0707504 and 2021YFC0866100); the Health and Medical Research Fund (19181012, COVID190123, 20190572, COVID1903010-4 and COVID1903010-7), the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region; Research Grants Council General Research Fund (17117422); Innovation and Technology Fund (ITF), The Government of the Hong Kong Special Administrative Region; the University Development Fund and Li Ka Shing Faculty of Medicine Matching Fund from the University of Hong Kong to the AIDS Institute; Shenzhen Science and Technology Program (JSGG20200225151410198); the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for Department of Health of the Hong Kong Special Administrative Region Government; Sanming Project of Medicine in Shenzhen, China (SZSM201911014); the High Level-Hospital Program, Health Commission of Guangdong Province, China; the research project of Hainan academician innovation platform (YSPTZX202004); and the Hainan talent development project (SRC200003); L.A.C's team was supported by the Urgence COVID-19 Fundraising Campaign of Institute Pasteur (TROPICORO project). The study was also supported by generous donations of the Friends of Hope Education Fund, Lee Wan Keung Charity Foundation Limited, Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Richard Yu and Carol Yu, May Tam Mak Mei Yin, Hong Kong Sanatorium & Hospital, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie & George Ho Charitable Foundation, Perfect Shape Medical Limited, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation Limited, Betty Hing-Chu Lee, Ping Cham So, and Lo Ying Shek Chi Wai Foundation. Z.C.’s team was also partly supported by the Theme-Based Research Scheme (T11-706/18-N and T11/709/21-N) and Wellcome Trust (P86433).