Recapitulating infection, thermal sensitivity and antiviral treatment of seasonal coronaviruses in human airway organoids.
Recapitulating infection, thermal sensitivity and antiviral treatment of seasonal coronaviruses in human airway organoids.
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人类呼吸道类器官中季节性冠状病毒的复发感染、热敏感性和抗病毒治疗。
DOI：
10.1016/j.ebiom.2022.104132
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发表时间：
2022-07
期刊：
影响因子：
11.1
通讯作者：
Pan, Qiuwei
中科院分区：
文献类型：
--
作者：
Li, Pengfei;Wang, Yining;Lamers, Mart M.;Lavrijsen, Marla;Iriondo, Cinta;de Vries, Annemarie C.;Rottier, Robbert J.;Peppelenbosch, Maikel P.;Haagmans, Bart L.;Pan, Qiuwei
关键词：
人类季节性冠状病毒通常会引起轻度上呼吸道感染，但在特定人群中会出现严重并发症。对季节性冠状病毒的研究有限，并且在很大程度上缺乏可靠的实验模型。本研究旨在建立基于人类气道类器官（hAOs）的季节性冠状病毒感染系统，并展示其在研究病毒-宿主相互作用和治疗开发中的应用。测试了季节性冠状病毒229 E、OC 43和NL 63在具有未分化或分化表型的三维培养的hAO中的感染。在33 °C和37 °C下分析病毒复制和产生的动力学。在各种条件下在hAO中通过RNA测序进行全基因组转录组分析。测试了两种批准用于治疗COVID 19的药物莫努匹拉韦和瑞德西韦的抗病毒活性。HAO有效地支持季节性冠状病毒229 E、OC 43和NL 63的复制和感染性病毒产生。有趣的是，与37 °C相比，季节性冠状病毒在33 °C下的复制效率更高，导致病毒复制水平高出10倍以上。全基因组转录组分析揭示了与37 °C温度相比，33 °C下感染触发的宿主反应的不同模式。莫努匹韦和Remdesivir的治疗剂量依赖性地抑制hAO中229 E、OC 43和NL 63的复制。HAO能够模拟229 E、OC 43和NL 63感染。有趣的发现是，与上呼吸道相似的较低温度有利于病毒复制，这可能有助于更好地了解季节性冠状病毒的发病机制和传播性。基于HAOs的创新模型将促进针对季节性冠状病毒感染的研究和治疗开发。这项研究得到了荷兰科学研究组织和荷兰癌症协会青年研究者资助（10140）的VIDI资助（编号91719300）的支持，以及荷兰卫生研究与发展组织的ZonMw COVID项目（114025011），
Human seasonal coronaviruses usually cause mild upper-respiratory tract infection, but severe complications can occur in specific populations. Research into seasonal coronaviruses is limited and robust experimental models are largely lacking. This study aims to establish human airway organoids (hAOs)-based systems for seasonal coronavirus infection and to demonstrate their applications in studying virus-host interactions and therapeutic development. The infections of seasonal coronaviruses 229E, OC43 and NL63 in 3D cultured hAOs with undifferentiated or differentiated phenotypes were tested. The kinetics of virus replication and production was profiled at 33 °C and 37 °C. Genome-wide transcriptome analysis by RNA sequencing was performed in hAOs under various conditions. The antiviral activity of molnupiravir and remdesivir, two approved medications for treating COVID19, was tested. HAOs efficiently support the replication and infectious virus production of seasonal coronaviruses 229E, OC43 and NL63. Interestingly, seasonal coronaviruses replicate much more efficiently at 33 °C compared to 37 °C, resulting in over 10-fold higher levels of viral replication. Genome-wide transcriptomic analyses revealed distinct patterns of infection-triggered host responses at 33 °C compared to 37 °C temperature. Treatment of molnupiravir and remdesivir dose-dependently inhibited the replication of 229E, OC43 and NL63 in hAOs. HAOs are capable of modeling 229E, OC43 and NL63 infections. The intriguing finding that lower temperature resembling that in the upper respiratory tract favors viral replication may help to better understand the pathogenesis and transmissibility of seasonal coronaviruses. HAOs-based innovative models shall facilitate the research and therapeutic development against seasonal coronavirus infections. This research is supported by funding of a VIDI grant (No. 91719300) from the Netherlands Organization for Scientific Research and the Dutch Cancer Society Young Investigator Grant (10140) to Q.P., and the ZonMw COVID project (114025011) from the Netherlands Organization for Health Research and Development to R.R.
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影响因子：
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影响因子：
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