The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.
The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.
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DOI：
10.1038/s41586-022-04421-w
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发表时间：
2022-03
期刊：
影响因子：
64.8
通讯作者：
Ablasser A
中科院分区：
文献类型：
--
作者：
Domizio JD;Gulen MF;Saidoune F;Thacker VV;Yatim A;Sharma K;Nass T;Guenova E;Schaller M;Conrad C;Goepfert C;de Leval L;Garnier CV;Berezowska S;Dubois A;Gilliet M;Ablasser A
COVID-19是由SARS-CoV-2感染引起的，其特征是肺部病理和肺外并发症。I型干扰素（ifn）在COVID-19的发病机制中发挥重要作用（参考文献）。尽管I型ifn的快速诱导限制了病毒的传播，但在感染后期，I型ifn水平的持续增加与异常炎症和不良临床结果有关。本研究表明，控制胞质DNA免疫的环状GMP-AMP合成酶(cGAS) -干扰素基因刺激因子（STING）通路是COVID-19异常I型IFN反应的关键驱动因素（参考文献）。通过分析COVID-19皮肤表现，我们发现了一个sting依赖的I型IFN信号，该信号主要由内皮细胞损伤区域附近的巨噬细胞介导。此外，在组织破坏明显的COVID-19患者的肺样本中检测到cGAS-STING活性，并与I型IFN反应相关。肺芯片模型显示，除了巨噬细胞外，SARS-CoV-2感染还通过线粒体DNA释放激活内皮细胞中的cGAS-STING信号，从而导致细胞死亡和I型IFN的产生。在小鼠中，STING的药理抑制可减轻SARS-CoV-2诱导的严重肺部炎症，并改善疾病预后。总之，我们的研究建立了COVID-19病理性I型IFN反应的机制基础，并揭示了开发宿主导向治疗方法的原则。cGAS-STING途径在严重COVID-19的发病机制中发挥核心作用，通过驱动在SARS-CoV-2感染后期发生的I型干扰素增加。
COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs ). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome. Here we show that the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. ). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS–STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS–STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics. The cGAS–STING pathway has a central role in the pathogenesis of severe COVID-19 by driving the increase in type I interferons that occurs in the later stages of SARS-CoV-2 infection.
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DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
24.8
作者：
Lee, Jeong Seok;Park, Seongwan;Shin, Eui-Cheol
通讯作者：
Shin, Eui-Cheol
影响因子：
46.9
作者：
Chua, Robert Lorenz;Lukassen, Soeren;Eils, Roland
通讯作者：
Eils, Roland
DOI：
10.1038/s41577-021-00536-9
发表时间：
2021-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Bonaventura A;Vecchié A;Dagna L;Martinod K;Dixon DL;Van Tassell BW;Dentali F;Montecucco F;Massberg S;Levi M;Abbate A
通讯作者：
Abbate A