Epigenetic regulation by nitrosative stress as a potential mechanism of long COVID

After recovering from COVID-19, some patients develop post-acute sequelae known as long COVID; however, the underlying mechanisms remain poorly understood. SARS-CoV-2 infection drives the aberrant expression of inducible nitric oxide synthase, triggering excessive nitric oxide generation. Here, we showed the direct evidence of the pathophysiological relevance of nitrosative stress in long COVID with measuring total S-nitrosylated protein levels in the plasma of long COVID patients. We found that the non-canonical activation of hypoxia-inducible factor (HIF) via DNA hypomethylation through S-nitrosylation of DNA methyltransferase, resulting in epigenetic gene upregulation of target genes in normal human cells. Remarkably, the expression levels of genes showed the sensitivity against specific inhibitor of S-nitrosylation of DNMT3B were significantly elevated in long COVID patients. Collectively, these findings suggest that nitrosative stress, particularly epigenetic gene regulation, is a potential mechanism of long COVID.

部分新冠病毒感染康复患者会罹患被称为长新冠（long COVID）的急性后后遗症，但目前其潜在发病机制仍不甚明晰。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染可诱导诱导型一氧化氮合酶（inducible nitric oxide synthase）异常表达，进而引发一氧化氮的过量生成。本研究通过检测长新冠患者血浆中的总S-亚硝基化蛋白（S-nitrosylated protein）水平，为硝化应激与长新冠的病理生理学相关性提供了直接证据。我们发现，通过DNA甲基转移酶（DNA methyltransferase）的S-亚硝基化作用介导DNA低甲基化，可使缺氧诱导因子（hypoxia-inducible factor, HIF）发生非经典激活，进而在正常人体细胞中引发靶基因的表观遗传上调。尤为值得关注的是，长新冠患者体内那些对DNA甲基转移酶3B（DNMT3B）的S-亚硝基化特异性抑制剂具有敏感性的基因，其表达水平显著升高。综上，本研究结果表明，硝化应激尤其是表观遗传基因调控，或是长新冠的潜在发病机制。