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

TY - JOUR

T1 - Human respiratory organoids sustained reproducible propagation of human rhinovirus C and elucidation of virus-host interaction

AU - Li, Cun

AU - Yu, Yifei

AU - Wan, Zhixin

AU - Chiu, Man Chun

AU - Huang, Jingjing

AU - Zhang, Shuxin

AU - Zhu, Xiaoxin

AU - Lan, Qiaoshuai

AU - Deng, Yanlin

AU - Zhou, Ying

AU - Xue, Wei

AU - Yue, Ming

AU - Cai, Jian-Piao

AU - Yip, Cyril Chik-Yan

AU - Wong, Kenneth Kak-Yuen

AU - Liu, Xiaojuan

AU - Yu, Yang

AU - Huang, Lin

AU - Chu, Hin

AU - Chan, Jasper Fuk-Woo

AU - Clevers, Hans

AU - Yuen, Kwok Yung

AU - Zhou, Jie

N1 - © 2024. The Author(s).

PY - 2024/12/30

Y1 - 2024/12/30

N2 - 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.

AB - 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.

KW - Humans

KW - Organoids/virology

KW - Immunity, Innate

KW - Host-Pathogen Interactions

KW - Antiviral Agents/pharmacology

KW - Picornaviridae Infections/virology

KW - Enterovirus/physiology

KW - Respiratory System/virology

KW - Virus Replication

KW - Virus Cultivation/methods

KW - Poly I-C/pharmacology

U2 - 10.1038/s41467-024-55076-2

DO - 10.1038/s41467-024-55076-2

M3 - Article

C2 - 39738014

SN - 2041-1723

VL - 15

SP - 10772

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -