SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation.
SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation.
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SARS-CoV-2 通过 caspase-8 激活引发炎症反应和细胞死亡
DOI：
10.1038/s41392-020-00334-0
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发表时间：
2020-10-09
影响因子：
39.3
通讯作者：
Peng K
中科院分区：
文献类型：
--
作者：
Li S;Zhang Y;Guan Z;Li H;Ye M;Chen X;Shen J;Zhou Y;Shi ZL;Zhou P;Peng K
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染可导致危重患者呼吸系统疾病和多器官功能衰竭。尽管病毒引起的肺损伤和炎性细胞因子风暴被认为与2019冠状病毒病（COVID-19）的临床表现直接相关，但病毒引发的炎症反应的潜在机制目前尚不清楚。在这里，我们报告说，SARS-CoV-2感染激活caspase-8，触发细胞凋亡和炎症细胞因子在肺上皮细胞的加工。经处理的炎性细胞因子通过病毒诱导的坏死性凋亡途径释放。在SARS-CoV-2感染HFH 4-hACE 2转基因小鼠模型的肺切片中也观察到病毒诱导的细胞凋亡、坏死性凋亡和炎症激活，该模型是研究SARS-CoV-2发病机制的有效模型。此外，对致死性COVID-19患者的尸检肺切片的分析显示，不仅细胞凋亡和坏死性凋亡，而且大量炎性细胞浸润、坏死细胞碎片和肺间质纤维化，这是肺中典型的免疫发病机制。SARS-CoV-2感染触发了细胞死亡途径和caspase-8依赖性炎症反应的双重模式，可能导致COVID-19患者的肺损伤。这些发现可能有助于开发治疗COVID-19的治疗策略。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.
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DOI：
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发表时间：
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期刊：
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