Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; STING; aspirin; cGAMP; interferon; lymphocyte; lymphopenia.

Figure 1

Consequences of STING over-activation on antigen presenting cells and T cells following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection. In antigen presenting cells (left), due to poor virus control by RNA sensors (including RIG-1, and MDA5) and despite the help of STING (red hexagon), SARS-CoV-2 induces delayed cell damages, with mitochondrial DNA and dsDNA release. It can add to damaged self-DNA secondary to ageing and/or obesity/diabetes. cGAS catalyzes those self-DNA in cyclic nucleotides, mainly cGAMP, which in turn activates STING (red hexagon). This activation of STING may be enhanced by: i) a lack of miRNAs, (like miR-576-3p, which normally suppress STING translation); ii) excess of IFIT3, which interacts with STING gene to promote its expression. Binding of cGAMP to STING first induces activation of the STING-TBK1-IRF3 pathway, leading to IFN-I synthesis. In COVID-19, the SARS-CoV-2 NSP 3 and 16 lower this IFN secretion, but IFN enhances expression of ACE2 on cell membrane. cGAMP, which can be released to by-stander cells through viral exosomes, can also be transmitted by B cells (low), to activated T cells (right), through specific channels. Independently of the STING-TBK1-IRF3 pathway, binding of cGAMP to STING can also: i) induce pyroptosis; ii) promote autophagy and lymphopenia; iii) activate NF-κB and both TNF and IL-6 synthesis. SARS-CoV-2 NSP 9 and 10 still enhances IL-6 release through inhibition of NKRF. Some beta-coronaviruses can also impede ULK1 and its negative feed-back loop, further enhancing IL-6 secretion. Excess of cGAMP can be internalized by by-stander activated CD4+ and CD8+T cells, which highly express the cGAMP importer SLC19A1. Therefore, even without infection of T lymphocytes, STING activation could also occur in activated T lymphocytes, especially those already stressed by a continuous activation by their hyper-responsive TCR. Defective retro-control of STING (dashed red loop) by IL-6 (see above) could still enhance STING activation in severe COVID-19. In activated T cells, STING overactivation leads to autophagy, up to lymphocyte death. This contributes much to the lymphopenia observed in rodent and human gain of function of STING models, and perhaps also in COVID-19, with subsequent poor virus control.