Interferon gene expression declines over time post-COVID infection and in long COVID patients

Interferons (IFNs) represent a first-line defense against viruses and other pathogens. It has been shown that an impaired and uncontrolled release of these glycoproteins can result in tissue damage and explain severe progression of coronavirus disease 2019 (COVID-19). However, their potential role in Long-COVID syndrome (LC) remains debateable. The objective of the present study is to shed further light on the possible role of IFNs (and related genes) gene expression patterns in the progression of COVID-19 and LC patients. We carried out a multi-cohort study by analyzing the IFN gene expression patterns (using different IFN gene signatures) in five cohorts of acute COVID-19 (<i>n</i> = 541 samples) and LC patients (<i>n</i> = 188), and compared them to patterns observed in three autoimmune diseases (systemic lupus erythematous [<i>n</i> = 242], systemic sclerosis [<i>n</i> = 91], and Sjögren’s syndrome [<i>n</i> = 282]). The data show that, while the interferon signatures are strongly upregulated in severe COVID-19 patients and autoimmune diseases, it decays with the time from symptoms onset and in LC patients. Differential pathway analysis of IFN-related terms indicates an over activation in autoimmune diseases (IFN-I/II) and severe COVID-19 (IFN-I/II/III), while these pathways are mostly inactivated or downregulated in LC (IFN-I/III). By analyzing six proteomic LC datasets, we did not find evidence of a role of IFNs in this condition. Our findings suggest a potential role of cytokine exhaustion mediated by IFN gene expression inactivation as a possible driver of LC.

干扰素（Interferons, IFNs）是机体对抗病毒与其他病原体的第一道防线。已有研究证实，这类糖蛋白的释放受损且失控时，可引发组织损伤，也是2019冠状病毒病（coronavirus disease 2019, COVID-19）病情恶化的关键诱因。然而，其在长新冠综合征（Long-COVID syndrome, LC）中的潜在作用仍存在争议。本研究旨在进一步阐明干扰素（及相关基因）的基因表达谱在COVID-19与长新冠患者病情进展中的潜在作用。本研究开展了一项多队列研究，分析了5个急性COVID-19队列（共541份样本）与188名长新冠患者的干扰素基因表达谱（采用不同的干扰素基因特征），并将上述表达谱与3种自身免疫性疾病患者的表达谱进行对比：分别为系统性红斑狼疮（242份样本）、系统性硬化症（91份样本）及干燥综合征（282份样本）。研究数据显示，尽管干扰素特征在重症COVID-19患者与自身免疫性疾病患者中均显著上调，但长新冠患者体内该特征会随症状发作后的时间推移逐渐减弱。对干扰素相关条目开展的差异通路分析表明，自身免疫性疾病（I型/II型干扰素）与重症COVID-19（I型/II型/III型干扰素）中存在干扰素通路的过度激活，而长新冠患者体内此类通路大多处于失活或下调状态（仅涉及I型/III型干扰素）。通过分析6组长新冠蛋白质组数据集，本研究未发现干扰素在此类病症中发挥作用的相关证据。本研究结果提示，由干扰素基因表达失活介导的细胞因子耗竭，可能是长新冠的潜在驱动因素。