Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening.
Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening.
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DOI：
10.1016/j.celrep.2021.109218
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发表时间：
2021-06-08
期刊：
影响因子：
8.8
通讯作者：
Sato T
中科院分区：
文献类型：
--
作者：
Ebisudani T;Sugimoto S;Haga K;Mitsuishi A;Takai-Todaka R;Fujii M;Toshimitsu K;Hamamoto J;Sugihara K;Hishida T;Asamura H;Fukunaga K;Yasuda H;Katayama K;Sato T
虽然严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染的主要细胞靶点被认为是肺泡细胞，但由于缺乏易处理的培养系统，因此无法建立临床相关的SARS-CoV-2感染模型。本研究建立了一种高效的人肺泡细胞培养方法和基于肺泡细胞的SARS-CoV-2药物检测平台。肺泡微球以Wnt和R-spondin依赖性方式表现出惰性生长。基因表达、免疫荧光和电子显微镜分析揭示了肺泡球中肺泡细胞的存在。肺泡球表达ACE 2，并允许SARS-CoV-2在感染3天内繁殖近10万倍。用于治疗人类免疫缺陷病毒（HIV）感染的蛋白酶抑制剂洛匹那韦（lopinavir）和奈非那韦（nelfinavir）对SARS-CoV-2具有适度的抗病毒作用，而核苷酸前药remdesivir在与循环药物水平相当的浓度下显示出抗病毒作用。这些结果证明了肺泡培养系统用于开发对抗SARS-CoV-2的治疗剂的有效性。Ebisudani等人建立临床相关人肺泡培养平台。他们将这种基于球体的系统应用于SARS-CoV-2感染。SARS-CoV-2在肺泡球中的复制使得能够评估抗病毒药物的抑制作用，例如使用Remdesivir。该模型将有助于准确评估针对COVID-19的候选药物。
Although the main cellular target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be alveolar cells, the absence of their tractable culture system precludes the development of a clinically relevant SARS-CoV-2 infection model. Here, we establish an efficient human alveolosphere culture method and sphere-based drug testing platform for SARS-CoV-2. Alveolospheres exhibit indolent growth in a Wnt- and R-spondin-dependent manner. Gene expression, immunofluorescence, and electron microscopy analyses reveal the presence of alveolar cells in alveolospheres. Alveolospheres express ACE2 and allow SARS-CoV-2 to propagate nearly 100,000-fold in 3 days of infection. Whereas lopinavir and nelfinavir, protease inhibitors used for the treatment of human immunodeficiency virus (HIV) infection, have a modest anti-viral effect on SARS-CoV-2, remdesivir, a nucleotide prodrug, shows an anti-viral effect at the concentration comparable with the circulating drug level. These results demonstrate the validity of the alveolosphere culture system for the development of therapeutic agents to combat SARS-CoV-2. Ebisudani et al. establish a clinically relevant culture platform for human alveolus. They apply this sphere-based system to SARS-CoV-2 infection. The reproduction of SARS-CoV-2 in alveolospheres enables evaluation of anti-viral drug inhibitory effects, such as with remdesivir. This model will contribute to the accurate evaluation of candidate drugs against COVID-19.
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