Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months following acute SARS-CoV-2 infection. The aetiologies may include persistent inflammation, unresolved tissue damage or delayed clearance of viral protein or RNA, but the biological differences they represent are not fully understood. Here we evaluate the serum proteome in samples, longitudinally collected from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection, in comparison to samples from symptomatically recovered SARS-CoV-2 infected and uninfected individuals. Our analysis indicates heterogeneity in PASC and identified subsets with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), appear to be the most differentially enriched signaling pathways, distinguishing a group of patients characterized also by a persistent neutrophil activation signature. These findings help to clarify biological diversity within PASC, identify participants with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance, including a protein panel that we propose as having diagnostic utility for differentiating inflammatory and non-inflammatory PASC.

长期新冠肺炎或 SARS-CoV-2 急性后遗症 (PASC) 是一种临床综合征，具有多种症状，在急性 SARS-CoV-2 感染后可能持续数月。病因可能包括持续性炎症、未解决的组织损伤或病毒蛋白或RNA清除延迟，但它们所代表的生物学差异尚未完全了解。在这里，我们评估了从 55 名 PASC 个体中纵向收集的样本中的血清蛋白质组，这些样本在急性感染发作后症状持续 ≥ 60 天，并与症状恢复的 SARS-CoV-2 感染者和未感染者的样本进行比较。我们的分析表明 PASC 的异质性，并确定了具有明显持续性炎症特征的子集。 II 型干扰素信号传导和典型的 NF-κB 信号传导（特别是与 TNF 相关）似乎是差异最丰富的信号传导途径，区分了一组还具有持续性中性粒细胞激活特征的患者。这些发现有助于阐明 PASC 内的生物多样性，识别具有持续炎症分子证据的参与者，并突出可能具有诊断或治疗相关性的主要途径，包括我们建议具有区分炎症和非炎症 PASC 诊断实用性的蛋白质组。