tetano
Editor, Senior Moderator
Cell Mol Immunol
. 2023 Mar 2.
doi: 10.1038/s41423-023-00985-3. Online ahead of print.
A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19
Lin Xia[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Lun-Zhi Yuan[SUP] #[/SUP][SUP] 3 [/SUP], Ya-Hong Hu[SUP] #[/SUP][SUP] 1 2 [/SUP], Jun-Yi Liu[SUP] #[/SUP][SUP] 3 [/SUP], Guo-Sheng Hu[SUP] #[/SUP][SUP] 1 2 [/SUP], Ruo-Yao Qi[SUP] #[/SUP][SUP] 3 [/SUP], Tian-Ying Zhang[SUP] 3 [/SUP], Hua-Long Xiong[SUP] 3 [/SUP], Zao-Zao Zheng[SUP] 1 2 [/SUP], Hong-Wei Lin[SUP] 3 [/SUP], Jia-Mo Zhang[SUP] 1 2 [/SUP], Chao Yu[SUP] 3 [/SUP], Ming Zhou[SUP] 3 [/SUP], Jian Ma[SUP] 3 [/SUP], Tong Cheng[SUP] 3 [/SUP], Ri-Rong Chen[SUP] 4 [/SUP], Yi Guan[SUP] 4 [/SUP], Ning-Shao Xia[SUP] 5 [/SUP], Wen Liu[SUP] 6 7 [/SUP]
Affiliations
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.
Keywords: CAR-T; COVID-19; NF-κB pathway; SARS-CoV-2; anti-inflammation.
. 2023 Mar 2.
doi: 10.1038/s41423-023-00985-3. Online ahead of print.
A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19
Lin Xia[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Lun-Zhi Yuan[SUP] #[/SUP][SUP] 3 [/SUP], Ya-Hong Hu[SUP] #[/SUP][SUP] 1 2 [/SUP], Jun-Yi Liu[SUP] #[/SUP][SUP] 3 [/SUP], Guo-Sheng Hu[SUP] #[/SUP][SUP] 1 2 [/SUP], Ruo-Yao Qi[SUP] #[/SUP][SUP] 3 [/SUP], Tian-Ying Zhang[SUP] 3 [/SUP], Hua-Long Xiong[SUP] 3 [/SUP], Zao-Zao Zheng[SUP] 1 2 [/SUP], Hong-Wei Lin[SUP] 3 [/SUP], Jia-Mo Zhang[SUP] 1 2 [/SUP], Chao Yu[SUP] 3 [/SUP], Ming Zhou[SUP] 3 [/SUP], Jian Ma[SUP] 3 [/SUP], Tong Cheng[SUP] 3 [/SUP], Ri-Rong Chen[SUP] 4 [/SUP], Yi Guan[SUP] 4 [/SUP], Ning-Shao Xia[SUP] 5 [/SUP], Wen Liu[SUP] 6 7 [/SUP]
Affiliations
- PMID: 36864189
- DOI: 10.1038/s41423-023-00985-3
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.
Keywords: CAR-T; COVID-19; NF-κB pathway; SARS-CoV-2; anti-inflammation.