Rheumatology Department, Nantes University Hospital, Nantes, France.
Rheumatology Department & Inserm UMR 1132 (centre Viggo Petersen), Hôpital Lariboisière, Université de Paris, Paris, France.
Front Immunol. 2020 Dec 1;11:607069. doi: 10.3389/fimmu.2020.607069. eCollection 2020.
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.
当宿主识别微生物 DNA 或自身 DNA 时，环状鸟苷酸-腺苷酸合酶（cGAS）催化环状二核苷酸 cGAMP 的产生。cGAMP 是 STING 的主要激活剂，干扰素基因刺激物，通过 STING-TBK1-IRF3 途径导致干扰素的合成。STING 也是 NF-κB 和自噬的激活中心。本综述详细描述了严重 2019 年冠状病毒病（COVID-19）患者 T 细胞和 B 细胞反应与 STING 功能获得（STING 相关血管病伴婴儿期发病，SAVI 综合征）动物或人类模型之间的惊人相似性。这些相似性可能是由于严重急性呼吸综合征冠状病毒（SARS-CoV-2）感染后 DNA 损伤以及 STING 在 SARS-CoV-2 控制中的异常作用，导致严重 COVID-19 患者中 STING 延迟激活的进一步线索。在早期阶段，严重 COVID-19 和 SAVI 综合征中均注意到 Th2 分化；然后，由于 TCR 过度反应，观察到 CD4+和 CD8+T 细胞功能衰竭/衰老模式。T 细胞延迟过度反应可能导致肺炎和细胞因子过度产生 IL-6 的延迟分泌。最后，STING 过度激活导致 SAVI 综合征中 CD4+和 CD8+T 淋巴细胞进行性减少，这与严重 COVID-19 中观察到的情况相似。SARS-CoV-2 的主要受体 ACE2 在免疫细胞中很少表达，尚未证明某些人类淋巴细胞可以通过 CD147 或 CD26 感染 SARS-CoV-2。然而，表达于人类 T 细胞中的 STING 可能在感染的抗原呈递细胞向激活的 CD4+和 CD8+T 淋巴细胞过度转移 cGAMP 后被触发。事实上，这些淋巴细胞高度表达 cGAMP 导入器 SLC19A1。尽管 STING 不在人类 B 细胞中表达，但在 COVID-19 或 SAVI 综合征中，B 细胞计数的影响要小得多。在严重 COVID-19 患者中识别出延迟的 STING 过度激活可能会促使使用已经设计好的针对 STING 的特定小分子抑制剂或阿司匹林（抑制 cGAS）来靶向 STING。
