Human respiratory organoids sustained reproducible propagation of human rhinovirus C and elucidation of virus-host interaction

Cun Li, Yifei Yu, Zhixin Wan, Man Chun Chiu, Jingjing Huang, Shuxin Zhang, Xiaoxin Zhu, Qiaoshuai Lan, Yanlin Deng, Ying Zhou, Wei Xue, Ming Yue, Jian-Piao Cai, Cyril Chik-Yan Yip, Kenneth Kak-Yuen Wong, Xiaojuan Liu, Yang Yu, Lin Huang, Hin Chu, Jasper Fuk-Woo Chan, Hans Clevers, Kwok Yung Yuen and Jie Zhou ()
Additional contact information
Cun Li: Pokfulam
Yifei Yu: Pokfulam
Zhixin Wan: Pokfulam
Man Chun Chiu: Pokfulam
Jingjing Huang: Pokfulam
Shuxin Zhang: Pokfulam
Xiaoxin Zhu: Pokfulam
Qiaoshuai Lan: Pokfulam
Yanlin Deng: Pokfulam
Ying Zhou: Pokfulam
Wei Xue: Pokfulam
Ming Yue: Pokfulam
Jian-Piao Cai: Pokfulam
Cyril Chik-Yan Yip: Pokfulam
Kenneth Kak-Yuen Wong: and Queen Mary Hospital
Xiaojuan Liu: Peking University Third Hospital
Yang Yu: Peking University Third Hospital
Lin Huang: BiomOrgan Ltd
Hin Chu: Pokfulam
Jasper Fuk-Woo Chan: Pokfulam
Hans Clevers: and University Medical Center (UMC) Utrecht
Kwok Yung Yuen: Pokfulam
Jie Zhou: Pokfulam

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The lack of a robust system to reproducibly propagate HRV-C, a family of viruses refractory to cultivation in standard cell lines, has substantially hindered our understanding of this common respiratory pathogen. We sought to develop an organoid-based system to reproducibly propagate HRV-C, and characterize virus-host interaction using respiratory organoids. We demonstrate that airway organoids sustain serial virus passage with the aid of CYT387-mediated immunosuppression, whereas nasal organoids that more closely simulate the upper airway achieve this without any intervention. Nasal organoids are more susceptible to HRV-C than airway organoids. Intriguingly, upon HRV-C infection, we observe an innate immune response that is stronger in airway organoids than in nasal organoids, which is reproduced in a Poly(I:C) stimulation assay. Treatment with α-CDHR3 and antivirals significantly reduces HRV-C viral growth in airway and nasal organoids. Additionally, an organoid-based immunofluorescence assay is established to titrate HRV-C infectious particles. Collectively, we develop an organoid-based system to reproducibly propagate the poorly cultivable HRV-C, followed by a comprehensive characterization of HRV-C infection and innate immunity in physiologically active respiratory organoids. The organoid-based HRV-C infection model can be extended for developing antiviral strategies. More importantly, our study has opened an avenue for propagating and studying other uncultivable human and animal viruses.

Date: 2024
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DOI: 10.1038/s41467-024-55076-2

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