A SARS-CoV-2-specific CAR-T-cell model identifies felodipine,fasudil,imatinib,and caspofungin as potential treatments for lethal COVID-19  

作　　者：in Xia Lun-zhi Yuan Ya-hong Hu Jun-yi Liu Guo-sheng Hu Ruo-yao Qi Tian-ying Zhang Hua-long Xiong Zao-zao Zheng Hong-wei Lin Jia-mo Zhang Chao Yu Ming Zhou Jian Ma Tong Cheng Ri-rong Chen Yi Guan Ning-shao Xia Wen Liu 

机构地区：[1]State Key Laboratory of Cellular Stress Biology,School of Pharmaceutical Sciences,Xiamen University,Xiang’an South Road,Xiamen,Fujian 361102,China [2]Fujian Provincial Key Laboratory of Innovative Drug Target Research,School of Pharmaceutical Sciences,Xiamen University,Xiang’an South Road,Xiamen,Fujian 361102,China [3]State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,National Institute of Diagnostics and Vaccine Development in Infectious Diseases,School of Life Sciences,School of Public Health,Xiamen University,Xiang’an South Road,Xiamen,Fujian 361102,China [4]State Key Laboratory of Emerging Infectious Diseases,School of Public Health,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong SAR,China.

出　　处：《Cellular & Molecular Immunology》2023年第4期351-364,共14页中国免疫学杂志（英文版）

基　　金：Fundamental Research Funds for the Central Universities(20720200104)to LX;the Ministry of Science and Technology of China(2020YFA0112300 and 2020YFA0803600);the National Natural Science Foundation of China(82125028,U22A20320,91953114,31871319,81761128015,and 81861130370);the Natural Science Foundation of Fujian Province of China(2020J02004);the Fundamental Research Funds for the Central University(20720190145 and 20720220003)to WL;the China Postdoctoral Science Foundation(2022M720119)to ZZZ.Part of Fig.6 was drawnbyusingFigdraw.

摘　　要：Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019(COVID-19)severity and lethality.However,drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed.Here,we constructed a SARS-CoV-2 spike protein-specific CAR,and human T cells infected with this CAR(SARS-CoV-2-S CAR-T)and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients,causing cytokine storm and displaying a distinct memory,exhausted,and regulatory T-cell phenotype.THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture.Based on this"two-cell"(CAR-T and THP1 cells)model,we screened an FDA-approved drug library and found that felodipine,fasudil,imatinib,and caspofungin were effective in suppressing the release of cytokines,which was likely due to their ability to suppress the NF-kB pathway in vitro.Felodipine,fasudi,imatinib,and caspofungin were further demonstrated,although to different extents,to attenuate lethal inflammation,ameliorate severe pneumonia,and prevent mortality in a SARS-CoV-2-infected Syrian hamster model,which were also linked to their suppressive role in inflammation.In summary,we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner.The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe,inexpensive,and easily accessible for immediateuseinmostcountries.

关 键 词：COVID-19 SARS-CoV-2 CAR-T anti-inflammation NF-kB pathway 

分 类 号：R563.1[医药卫生—呼吸系统]