02718nas a2200457   4500000000100000000000100001008004100002260001500043653003100058653002300089653003000112100001100142700001300153700001500166700001800181700001900199700001700218700001600235700001800251700001600269700001400285700001200299700001300311700001800324700002300342700002600365700001700391700001200408700001400420700001200434700002400446700001700470700001900487700001300506245013100519856005500650300001000705490000700715520152400722022001402246       2024                            d  c2024-12-3010aRespiratory Tract Diseases10aViral pathogenesis10aVirus–host interactions1 aCun Li1 aYifei Yu1 aZhixin Wan1 aMan Chun Chiu1 aJingjing Huang1 aShuxin Zhang1 aXiaoxin Zhu1 aQiaoshuai Lan1 aYanlin Deng1 aYing Zhou1 aWei Xue1 aMing Yue1 aJian-Piao Cai1 aCyril Chik-Yan Yip1 aKenneth Kak-Yuen Wong1 aXiaojuan Liu1 aYang Yu1 aLin Huang1 aHin Chu1 aJasper Fuk-Woo Chan1 aHans Clevers1 aKwok Yung Yuen1 aJie Zhou00aHuman respiratory organoids sustained reproducible propagation of human rhinovirus C and elucidation of virus-host interaction  uhttps://www.nature.com/articles/s41467-024-55076-2  a107720 v153 aThe 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.  a2041-1723