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- Publisher Website: 10.1038/s41423-023-00985-3
- Scopus: eid_2-s2.0-85149260738
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Article: A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19
Title | A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19 |
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Authors | |
Keywords | anti-inflammation CAR-T COVID-19 NF-κB pathway SARS-CoV-2 |
Issue Date | 1-Apr-2023 |
Publisher | Springer Nature [academic journals on nature.com] |
Citation | Cellular & Molecular Immunology, 2023, v. 20, n. 4, p. 351-364 How to Cite? |
Abstract | 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-κB pathway in vitro. Felodipine, fasudil, 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 immediate use in most countries. |
Persistent Identifier | http://hdl.handle.net/10722/337910 |
ISSN | 2023 Impact Factor: 21.8 2023 SCImago Journal Rankings: 4.838 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Xia, Lin | - |
dc.contributor.author | Yuan, Lun-zhi | - |
dc.contributor.author | Hu, Ya-hong | - |
dc.contributor.author | Liu, Jun-yi | - |
dc.contributor.author | Hu, Guo-sheng | - |
dc.contributor.author | Qi, Ruo-yao | - |
dc.contributor.author | Zhang, Tian-ying | - |
dc.contributor.author | Xiong, Hua-long | - |
dc.contributor.author | Zheng, Zao-zao | - |
dc.contributor.author | Lin, Hong-wei | - |
dc.contributor.author | Zhang, Jia-mo | - |
dc.contributor.author | Yu, Chao | - |
dc.contributor.author | Zhou, Ming | - |
dc.contributor.author | Ma, Jian | - |
dc.contributor.author | Cheng, Tong | - |
dc.contributor.author | Chen, Ri-rong | - |
dc.contributor.author | Guan, Yi | - |
dc.contributor.author | Xia, Ning-shao | - |
dc.contributor.author | Liu, Wen | - |
dc.date.accessioned | 2024-03-11T10:24:51Z | - |
dc.date.available | 2024-03-11T10:24:51Z | - |
dc.date.issued | 2023-04-01 | - |
dc.identifier.citation | Cellular & Molecular Immunology, 2023, v. 20, n. 4, p. 351-364 | - |
dc.identifier.issn | 1672-7681 | - |
dc.identifier.uri | http://hdl.handle.net/10722/337910 | - |
dc.description.abstract | <p>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-κB pathway in vitro. Felodipine, fasudil, 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 immediate use in most countries.<br></p> | - |
dc.language | eng | - |
dc.publisher | Springer Nature [academic journals on nature.com] | - |
dc.relation.ispartof | Cellular & Molecular Immunology | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | anti-inflammation | - |
dc.subject | CAR-T | - |
dc.subject | COVID-19 | - |
dc.subject | NF-κB pathway | - |
dc.subject | SARS-CoV-2 | - |
dc.title | A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19 | - |
dc.type | Article | - |
dc.identifier.doi | 10.1038/s41423-023-00985-3 | - |
dc.identifier.scopus | eid_2-s2.0-85149260738 | - |
dc.identifier.volume | 20 | - |
dc.identifier.issue | 4 | - |
dc.identifier.spage | 351 | - |
dc.identifier.epage | 364 | - |
dc.identifier.eissn | 2042-0226 | - |
dc.identifier.isi | WOS:000942953000001 | - |
dc.identifier.issnl | 1672-7681 | - |