Amerimmune, Fairfax, VA, USA.
Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York City, NY, USA.
Allergy. 2022 Jan;77(1):118-129. doi: 10.1111/all.14907. Epub 2021 Jun 2.
COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela.
Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease.
MATERIALS & METHODS: We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls.
Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition.
Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed.
Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.
COVID-19 可表现为淋巴细胞减少和异常复杂的多器官病理，可能引发长期后遗症。
鉴于炎性小体产物（如 caspase-1）在多种合并症的病理生理学中发挥作用，我们研究了 COVID-19 疾病谱中的各种半胱天冬酶。
我们评估了多种半胱天冬酶的转录状态，并使用流式细胞术，检测了 COVID-19 患者在疾病急性期和恢复期血液细胞中活性 caspase-1 的表达。非 COVID-19 患者患有各种合并症作为对照。
COVID-19 患者免疫细胞的单细胞 RNA-seq 数据显示，与对照相比，T 细胞、中性粒细胞、树突状细胞和嗜酸性粒细胞中的半胱天冬酶表达模式明显不同。与未暴露对照相比，住院 COVID-19 患者的 CD4+T 细胞中 caspase-1 上调。有持续症状（长途旅行者）的 post-COVID-19 患者也显示 CD4+T 细胞中的 caspase-1 活性上调，体外实验表明，用选择性的 pan-caspase 抑制剂可减弱这种上调。与对照相比，COVID-19 患者的红细胞中 caspase-3/7 水平升高，用半胱天冬酶抑制剂处理后降低。
我们的初步结果表明 COVID-19 中存在过度的半胱天冬酶反应，这可能促进与免疫相关的病理过程，导致严重后果。需要对 COVID-19 不同阶段的半胱天冬酶表达进行进一步的临床相关性研究。
pan-caspase 抑制可能成为改善或预防严重 COVID-19 的治疗策略。
