Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?
Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?
复制标题
DOI：
10.3389/fimmu.2020.607069
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Sibilia J
中科院分区：
文献类型：
--
作者：
Berthelot JM;Lioté F;Maugars Y;Sibilia J
在识别微生物DNA或自身DNA后，宿主的环GMP-AMP合酶（cGAS）催化环二核苷酸cGAMP的产生。cGAMP是STING的主要激活剂，干扰素基因的刺激剂，导致通过STING-TBK 1-IRF 3途径合成干扰素。STING也是NF-κB和自噬活化的中心。本综述详细介绍了2019年严重冠状病毒病（COVID-19）中T和B细胞反应与STING功能获得的动物或人类模型（SAVI综合征：婴儿期发作的STING相关血管病变）之间的惊人相似性。这些相似性可能是严重COVID-19患者中STING延迟激活的进一步线索，这是由于严重急性呼吸综合征冠状病毒（SARS-CoV-2）感染后的DNA损伤以及STING在SARS-CoV-2控制中的不寻常作用。在早期阶段，在严重的COVID-19和SAVI综合征中均观察到Th 2分化;然后，观察到由于TCR高反应性导致的CD 4+和CD 8 + T细胞功能衰竭/衰老模式。T细胞延迟的过度反应可导致肺炎和延迟的细胞因子分泌，并导致IL-6的过度产生。最后，STING过度激活在SAVI综合征中诱导进行性CD 4+和CD 8 + T淋巴细胞减少症，这与在严重COVID-19中观察到的情况相似。ACE 2是SARS-CoV-2的主要受体，在免疫细胞中很少表达，目前尚未证明某些人类淋巴细胞可以通过CD 147或CD 26被SARS-CoV-2感染。然而，在人类T细胞中表达的STING可能在cGAMP从感染的抗原呈递细胞过度转移到活化的CD 4+和CD 8 + T细胞淋巴细胞中后被触发。事实上，这些淋巴细胞高度表达cGAMP输入者SLC 19 A1。尽管STING在人B细胞中不表达，但在COVID-19或SAVI综合征中，B细胞计数受到的影响要小得多。在严重的COVID-19患者中识别延迟的STING过度激活可以促使用已经设计的特异性小分子抑制剂和/或抑制cGAS的阿司匹林靶向STING。
Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.
登录
查看更多内容
影响因子：
24.1
作者：
Guo N;Ye S;Zhang K;Yu X;Cui H;Yang X;Lin P;Lv M;Miao J;Zhang Y;Han Q;Zhang R;Chen Z;Zhu P
通讯作者：
Zhu P
多器官感染和SAR的发病机理。
影响因子：
15.3
作者：
Gu, Jiang;Gong, Encong;Zhang, Bo;Zheng, Jie;Gao, Zifen;Zhong, Yanfeng;Zou, Wanzhong;Zhan, Jun;Wang, Shenglan;Xie, Zhigang;Zhuang, Hui;Wu, Bingquan;Zhong, Haohao;Shao, Hongquan;Fang, Weigang;Gao, Dongshia;Pei, Fei;Li, Xingwang;He, Zhongpin;Xu, Danzhen;Shi, Xeying;Anderson, Virginia M;Leong, Anthony S-Y
通讯作者：
Leong, Anthony S-Y
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Diao, Bo;Wang, Chenhui;Chen, Yongwen
通讯作者：
Chen, Yongwen
影响因子：
14.2
作者：
Bouis, Delphine;Kirstetter, Peggy;Soulas-Sprauel, Pauline
通讯作者：
Soulas-Sprauel, Pauline