严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 及其疾病表现 COVID-19 对公共卫生的持久影响仍然很大。 SARS-CoV-2 感染 (PASC) 的急性后遗症影响着相当多的患者，损害了他们的生活质量。虽然细胞因子风暴在急性 COVID-19 中的作用已得到充分证实，但其对 PASC 病理生理学的贡献尚不完全清楚。本研究旨在分析体外刺激 Toll 样受体 (TLR) 通路后 PASC 患者的细胞因子谱，并将其与健康对照组进行比较。 2020年10月至2021年3月，布鲁格曼大学医院的临床研究单位将PASC患者纳入研究。从 50 名患者和 25 名健康志愿者身上采集全血样本。在五种不同条件下进行体外刺激后，使用多重方法测量细胞因子水平。与健康志愿者相比，PASC 患者的细胞因子水平显着降低，特别是在 TLR4（白细胞介素 [IL]-1α、IL-1β、IL-2、IL-10、干扰素 (IFN)α、IFNγ、IFNω 和肿瘤治疗后）坏死因子 (TNF)α) 和 TLR7/8（IL-1α、IL-1β、IFNα、IFNω、IFNγ 和 TNFα）通路刺激。主成分分析确定了两个不同的簇，表明 PASC 患者可能涉及 TLR4 和 TLR7/8 通路的免疫调节失调。我们的研究表明 TLR4 和 TLR7/8 通路在 PASC 的病理生理学中发挥作用。免疫的持续基础激活可以解释这些患者中细胞因子基础浓度高以及这些信号通路在特定刺激后反应幅度降低的原因。

The enduring impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease manifestation, COVID-19, on public health remains significant. Postacute sequelae of SARS-CoV-2 infection (PASC) affect a considerable number of patients, impairing their quality of life. While the role of the cytokine storm in acute COVID-19 is well established, its contribution to the pathophysiology of PASC is not fully understood. This study aimed to analyze the cytokine profile of patients with PASC following in vitro stimulation of Toll-like receptor (TLR) pathways, comparing them with a healthy control group. From October 2020 till March 2021, Brugmann University Hospital's clinical research unit included patients with PASC in the study. Whole blood samples were collected from 50 patients and 25 healthy volunteers. After in vitro stimulation under five different conditions, cytokine levels were measured using a multiplex method. Significantly decreased cytokine levels were observed in patients with PASC compared with healthy volunteers, particularly after TLR4 (interleukin [IL]-1α, IL-1β, IL-2, IL-10, interferon (IFN)α, IFNγ, IFNω, and tumor necrosis factor (TNF)α) and TLR7/8 (IL-1α, IL-1β, IFNα, IFNω, IFNγ, and TNFα) pathway stimulation. Principal component analysis identified two distinct clusters, suggesting a likely dysregulation of immunity involving TLR4 and TLR7/8 pathways in patients with PASC. Our study suggests that TLR4 and TLR7/8 pathways play a role in the pathophysiology of PASC. Continuous basal activation of immunity could explain the high basal concentrations of cytokines described in these patients and the decreased amplitude of response of these signaling pathways following specific stimulation.