ORIGINAL RESEARCH article
Front. Immunol.
Sec. Viral Immunology
Plasma proteomic profile reveals persistent immune activation in post-acute sequelae of SARS-CoV-2 infection (PASC)
Provisionally accepted
- 1Department of Public Health and Caring Sciences, Faculty of Medicine, Uppsala University, Uppsala, Sweden
- 2Praktikertjänst Health Care Centre Rosendal, Uppsala, Sweden
- 3Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- 4Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden
- 5The ME/CFS Collaborative Research Centre, Uppsala University, Uppsala, Sweden
- 6Analytical Chemistry and Neurochemistry, Department of Chemistry for Life Sciences, BMC, Uppsala University, Uppsala, Sweden
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Plasma proteomic profiling of 92 individuals with Post-Acute Sequelae of SARS-CoV-2 infection (PASC), assessed a mean of 34 months after acute infection, revealed a distinct inflammatory signature. Using proximity extension assay technology, 358 proteins were quantified, identifying 26 differentially expressed proteins (DEPs) in PASC: 23 upregulated and 3 downregulated. The most upregulated proteins were Oncostatin M (OSM) and IL-1 receptor antagonist (IL1RN). Additional increases were observed in IL-6, IL-12B, IL-2, CCL22, CSF3, CSF1, and HLA-DRA, as well as proteins involved in tissue remodeling and angiogenesis such as ANGPTL2 and TGFA. Random forest analysis confirmed IL1RN, OSM, ANGPTL2, HLA-DRA, and CLEC4A as strong discriminators between patients and controls. Gene set enrichment analysis demonstrated activation of multiple immune pathways, including Inflammatory Response, TNF-α/NF-κB signaling, IL-6/JAK/STAT3, IL-2/STAT5, and Allograft Rejection, indicating persistent activation of innate and adaptive immunity. STRING network analysis highlighted a tightly connected cytokine-driven inflammatory module. Plasma spike protein levels did not differ between patients and controls, suggesting that PASC-related inflammation may persist independently of ongoing viral replication. Overall, the findings indicate a consistent low-grade inflammatory state in PASC without evidence for distinct biological subtypes.
Keywords: chronic inflammation, cytokine signaling, Immune dysregulation, Plasma proteomics, post-acute sequelae of SARS-CoV-2 infection (PASC)
Received: 24 Dec 2025; Accepted: 04 Feb 2026.
Copyright: © 2026 Fineschi, Klar, Schuster, Bergquist and Dahl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Serena Fineschi
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