Fineschi Serena, Klar Joakim, Lopez Egido Juan Ramon, Schuster Jens, Bergquist Jonas, Kaden René, Dahl Niklas
Department of Public Health and Caring Sciences, Faculty of Medicine, Uppsala University, Uppsala, Sweden.
Östhammar Health Care Centre, Östhammar, Sweden.
Front Immunol. 2025 May 30;16:1589589. doi: 10.3389/fimmu.2025.1589589. eCollection 2025.
Post-acute sequelae of SARS-CoV-2 infection (PASC), also known as post-COVID-19 condition (here abbreviated as post-COVID) is an escalating global health issue. The aim of our study was to investigate the mechanisms and clinical manifestations of post-COVID following a mild SARS-CoV-2 infection.
We analyzed the gene expression profile in PBMCs from 60 middle-aged post-COVID patients and 50 age-matched controls at a median time of 28 months following a mild SARS-CoV-2 infection. The clinical assessments included intensity of post-COVID symptoms, physical and mental fatigue, depression and anxiety. Sixty-seven participants performed a mild exertion ergometer test with assessment of lactate concentrations. Transcriptome analysis was performed on mRNA selected by poly-A enrichment and SARS-CoV-2 RNA fragments were analyzed using the ARTIC protocol.
We identified 463 differentially expressed transcripts in PBMCs, of which 324 were upregulated and 129 downregulated in post-COVID patients. Upregulated genes in post-COVID individuals were enriched for processes involving JAK-STAT signaling, negative regulation of ubiquitination, IL9 signaling, and negative regulation of viral process, suggesting chronic inflammation. Downregulated genes were enriched for processes involving mitochondrial ATP synthesis, and oxidative phosphorylation, suggesting mitochondrial dysfunction. No SARS-CoV-2 gene fragments were detected in PBMCs of patients with post-COVID and no IFN genes were found differentially expressed in post-COVID patients. Post-COVID was associated with elevated lactate levels in blood, both at rest and after a short recovery phase following exertion, suggesting increased anaerobic activity in skeletal muscles. We did not find differences in the transcriptional profiles or clinical manifestations when comparing patients who contracted the infection from early SARS-CoV-2 variants with those who contracted the infection during the period when the Omicron variant was prevalent.
Our findings highlight molecular changes compatible with a persistent immune response in PBMCs of post-COVID subjects at a median follow-up of 28 months after a mild infection, supporting the hypothesis that post-COVID is a chronic inflammatory condition. The upregulation of JAK/STAT signaling suggests a potential therapeutic target in post-COVID.
新型冠状病毒感染后的急性后遗症（PASC），也称为新冠后状况（在此简称为新冠后），是一个日益严重的全球健康问题。我们研究的目的是调查轻度新型冠状病毒感染后新冠后的机制和临床表现。
我们分析了60名中年新冠后患者和50名年龄匹配的对照在轻度新型冠状病毒感染后中位时间28个月时外周血单个核细胞（PBMC）中的基因表达谱。临床评估包括新冠后症状的强度、身体和精神疲劳、抑郁和焦虑。67名参与者进行了轻度运动测力计测试并评估了乳酸浓度。对通过聚腺苷酸富集选择的mRNA进行转录组分析，并使用ARTIC方案分析新型冠状病毒RNA片段。
我们在PBMC中鉴定出463个差异表达的转录本，其中324个在新冠后患者中上调，129个下调。新冠后个体中上调的基因富集于涉及JAK-STAT信号传导、泛素化的负调控、IL9信号传导和病毒过程的负调控的过程，提示存在慢性炎症。下调的基因富集于涉及线粒体ATP合成和氧化磷酸化的过程，提示线粒体功能障碍。在新冠后患者的PBMC中未检测到新型冠状病毒基因片段，且未发现新冠后患者中IFN基因存在差异表达。新冠后与静息时以及运动后短恢复期后血液中乳酸水平升高相关，提示骨骼肌中无氧活动增加。在比较感染早期新型冠状病毒变体的患者与感染奥密克戎变体流行期间的患者时，我们未发现转录谱或临床表现存在差异。
我们的研究结果突出了在轻度感染后中位随访28个月时新冠后受试者PBMC中与持续免疫反应相符的分子变化，支持新冠后是一种慢性炎症状态的假说。JAK/STAT信号传导的上调提示了新冠后的一个潜在治疗靶点。
