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.

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，是干扰素基因的刺激剂，通过 STING-TBK1-IRF3 途径导致干扰素合成。 STING 也是 NF-κB 和自噬激活的枢纽。本综述详细介绍了 2019 年严重冠状病毒病 (COVID-19) 中的 T 细胞和 B 细胞反应与 STING 功能获得的动物或人类模型（SAVI 综合征：婴儿期发病的 STING 相关血管病变）之间的惊人相似性。这些相似之处可能是严重 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 DNA 损伤以及 STING 在 SARS-CoV-2 控制中的不寻常作用。在早期阶段，严重的 COVID-19 和 SAVI 综合征中都观察到 Th2 分化；然后，观察到由于 TCR 高反应性导致的 CD4+ 和 CD8+ T 细胞功能衰竭/衰老模式。 T 细胞延迟性过度反应可导致肺炎，并导致细胞因子分泌延迟并导致 IL-6 过量产生。最后，STING 过度激活会导致 SAVI 综合征中进行性 CD4+ 和 CD8+ T 淋巴细胞减少，这与严重 COVID-19 中观察到的情况相似。 ACE2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CD147或CD26感染SARS-CoV-2。然而，在人类 T 细胞中表达的 STING 可能在 cGAMP 从受感染的抗原呈递细胞过度转移到激活的 CD4+ 和 CD8+ 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 输入蛋白 SLC19A1。 尽管 STING 在人类 B 细胞中不表达，但无论是在 COVID-19 还是 SAVI 综合征中，B 细胞计数受到的影响要小得多。认识到重症 COVID-19 患者延迟的 STING 过度激活可能会促使使用已经设计的特定小分子抑制剂和/或抑制 cGAS 的阿司匹林来靶向 STING。