小柯机器人

科学家使用肺和结肠类器官鉴定出SARS-CoV-2的抑制剂
2020-10-31 21:08

近日,美国纽约大学Shuibing Chen等研究人员合作使用肺和结肠类器官鉴定出SARS-CoV-2的抑制剂。2020年10月28日,《自然》杂志在线发表了这项成果。

由于SARS-CoV-2主要感染呼吸道,因此研究人员开发了使用人类多能干细胞的肺类器官模型(hPSC-LOs)。hPSC-LOs,特别是Ⅱ型肺泡细胞,能够感染SARS-CoV-2,并在SARS-CoV-2感染后表现出强烈的趋化因子诱导作用,类似于在COVID-19患者中所见。这些患者中将近25%的人也有胃肠道表现,这与COVID-19结果恶化有关。因此,研究人员还产生了互补的hPSC衍生的结肠类器官(hPSC-COs),以探索结肠细胞对SARS-CoV-2感染的反应。研究人员发现多种结肠细胞类型,尤其是肠上皮细胞,表达ACE2,并能够感染SARS-CoV-2。
 
使用hPSC-LOs,研究人员对FDA批准的药物进行了高通量筛选,并确定了SARS-CoV-2的细胞进入抑制剂,包括伊马替尼,麦考酚酸(MPA)和奎纳克林二盐酸盐(QNHC)。这些药物在生理上相关的水平上的治疗显着抑制了hPSC-LOs和hPSC-COs的SARS-CoV-2感染。
 
总之,这些数据表明,SARS-CoV-2感染的hPSC-LOs和hPSC-COs可以用作研究SARS-CoV-2感染的疾病模型,并为筛选药物来鉴定候选COVID-19治疗剂提供了有价值的资源。
 
据了解,迫切需要使用与人类疾病相关的细胞来创建新颖的模型,以研究SARS-CoV-2生物学并促进药物筛选。
 
附:英文原文

Title: Identification of SARS-CoV-2 Inhibitors using Lung and Colonic Organoids

Author: Yuling Han, Xiaohua Duan, Liuliu Yang, Benjamin E. Nilsson-Payant, Pengfei Wang, Fuyu Duan, Xuming Tang, Tomer M. Yaron, Tuo Zhang, Skyler Uhl, Yaron Bram, Chanel Richardson, Jiajun Zhu, Zeping Zhao, David Redmond, Sean Houghton, Duc-Huy T. Nguyen, Dong Xu, Xing Wang, Jose Jessurun, Alain Borczuk, Yaoxing Huang, Jared L. Johnson, Yuru Liu, Jenny Xiang, Hui Wang, Lewis C. Cantley, Benjamin R. tenOever, David D. Ho, Fong Cheng Pan, Todd Evans, Huanhuan Joyce Chen, Robert E. Schwartz, Shuibing Chen

Issue&Volume: 2020-10-28

Abstract: There is an urgent need to create novel models using human disease-relevant cells to study SARS-CoV-2 biology and to facilitate drug screening. As SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs, particularly alveolar type II-like cells, are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes1. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high throughput screen of FDA-approved drugs and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid (MPA), and quinacrine dihydrochloride (QNHC). Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.

DOI: 10.1038/s41586-020-2901-9

Source: https://www.nature.com/articles/s41586-020-2901-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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