A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19.
Lin XiaLun-Zhi YuanYa-Hong HuJun-Yi LiuGuo-Sheng HuRuo-Yao QiTian-Ying ZhangHua-Long XiongZao-Zao ZhengHong-Wei LinJia-Mo ZhangChao YuMing ZhouJian MaTong ChengRi-Rong ChenYi GuanNing-Shao XiaWen LiuPublished in: Cellular & molecular immunology (2023)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- oxidative stress
- high throughput
- drug induced
- single cell
- diabetic rats
- signaling pathway
- primary care
- endothelial cells
- cell therapy
- anti inflammatory
- transcription factor
- cardiovascular events
- wastewater treatment
- gene expression
- inflammatory response
- bone marrow
- dna methylation
- early onset
- smoking cessation
- binding protein
- cell death
- nuclear factor
- immune response