{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:49:55Z","timestamp":1791917395610,"version":"4.3.4"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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-\u03b1\/NF-\u03baB 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1775044","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T06:30:38Z","timestamp":1771828238000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Plasma proteomic profile reveals persistent immune activation in post-acute sequelae of SARS-CoV-2 infection"],"prefix":"10.3389","volume":"17","author":[{"given":"Serena","family":"Fineschi","sequence":"first","affiliation":[{"name":"Department of Public Health and Caring Sciences, Faculty of Medicine, Uppsala University","place":["Uppsala, Sweden"]},{"name":"Praktikertj\u00e4nst Health Care Centre Rosendal","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joakim","family":"Klar","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University","place":["Uppsala, Sweden"]},{"name":"Department of Clinical Genetics, Uppsala University Hospital","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Schuster","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Bergquist","sequence":"additional","affiliation":[{"name":"Analytical Chemistry and Neurochemistry, Department of Chemistry for Life Sciences, BMC, Uppsala University","place":["Uppsala, Sweden"]},{"name":"The ME\/CFS Collaborative Research Centre at Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Dahl","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03173-6","article-title":"Long COVID science, research and policy","volume":"30","author":"Al-Aly","year":"2024","journal-title":"Nat Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01292-y","article-title":"Attributes and predictors of long COVID","volume":"27","author":"Sudre","year":"2021","journal-title":"Nat Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3904\/kjim.2024.217","article-title":"Cytokine profiles associated with persisting symptoms of post-acute sequelae of COVID-19","volume":"40","author":"Kwon","year":"2025","journal-title":"Korean J Intern Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e200003","DOI":"10.1212\/NXI.0000000000200003","article-title":"Plasma markers of neurologic injury and inflammation in people with self-reported neurologic postacute sequelae of SARS-coV-2 infection","volume":"9","author":"Peluso","year":"2022","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e2200031","DOI":"10.1002\/prca.202200031","article-title":"Plasma biomarkers for systemic inflammation in COVID-19 survivors","volume":"16","author":"Zhao","year":"2022","journal-title":"Proteomics Clin Appl"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01724-6","article-title":"Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2","volume":"25","author":"Yin","year":"2024","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s10020-023-00610-z","article-title":"Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning","volume":"29","author":"Patel","year":"2023","journal-title":"Mol Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1038\/s41590-025-02135-5","article-title":"Identification of soluble biomarkers that associate with distinct manifestations of long COVID","volume":"26","author":"Gao","year":"2025","journal-title":"Nat Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100663","article-title":"The IL-1\u03b2, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19","volume":"3","author":"Schulthei\u00df","year":"2022","journal-title":"Cell Rep Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1177\/17562864241229567","article-title":"Cytokines (IL1\u03b2, IL6, TNF\u03b1) and serum cortisol levels may not constitute reliable biomarkers to identify individuals with post-acute sequelae of COVID-19","volume":"17","author":"Fleischer","year":"2024","journal-title":"Ther Adv Neurol Disord"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(22)00127-8","article-title":"Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study","volume":"10","author":"Collaborative Group","year":"2022","journal-title":"Lancet Respir Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"3417","DOI":"10.1038\/s41467-023-38682-4.[PMID","article-title":"Persistent serum protein signatures define an inflammatory subcategory of long COVID","volume":"14","author":"Talla","year":"2023","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","first-page":"4201","DOI":"10.1038\/s41467-023-40012-7","article-title":"Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID","volume":"14","author":"Woodruff","year":"2023","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01778-0","article-title":"Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease","volume":"25","author":"Liew","year":"2024","journal-title":"Nat Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01838-z","article-title":"Post-acute sequelae of SARS-CoV-2 cardiovascular symptoms are associated with trace-level cytokines that affect cardiomyocyte function","volume":"9","author":"Sinclair","year":"2024","journal-title":"Nat Microbiol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-025-03837-0","article-title":"Distinct pro-inflammatory\/pro-angiogenetic signatures distinguish children with Long COVID from controls","author":"Buonsenso","year":"2025","journal-title":"Pediatr Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac722","article-title":"Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae","volume":"76","author":"Swank","year":"2023","journal-title":"Clin Infect Dis"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2023.10.24.23297114","DOI":"10.1101\/2023.10.24.23297114","article-title":"Plasma-based antigen persistence in the post-acute phase of SARS-CoV-2 infection","author":"Peluso","year":"2023","journal-title":"medRxiv"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e28568","DOI":"10.1002\/jmv.28568","article-title":"Persistent circulation of soluble and extracellular vesicle-linked Spike protein in individuals with postacute sequelae of COVID-19","volume":"95","author":"Craddock","year":"2023","journal-title":"J Med Virol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00703-9","article-title":"A clinical case definition of post-COVID-19 condition by a Delphi consensus","volume":"22","author":"Soriano","year":"2022","journal-title":"Lancet Infect Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1989.00520460115022","article-title":"The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus","volume":"46","author":"Krupp","year":"1989","journal-title":"Arch Neurol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3109\/02699050903452961","article-title":"A self-assessment questionnaire for mental fatigue and related symptoms after neurological disorders and injuries","volume":"24","author":"Johansson","year":"2010","journal-title":"Brain Inj"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.134.4.382","article-title":"A new depression scale designed to be sensitive to change","volume":"134","author":"Montgomery","year":"1979","journal-title":"Br J Psychiatry"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0447.1983.tb09716.x","article-title":"The hospital anxiety and depression scale","volume":"67","author":"Zigmond","year":"1983","journal-title":"Acta Psychiatr Scand"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2024.1435218","article-title":"Comprehensive MRI assessment reveals subtle brain findings in non-hospitalized post-COVID patients with cognitive impairment","author":"Fineschi","year":"2024","journal-title":"Front Neurosci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1589589","article-title":"Comprehensive transcriptome assessment in PBMCs of post-COVID patients at a median follow-up of 28 months after a mild COVID infection reveals upregulation of JAK\/STAT signaling and a prolonged immune response","volume":"16","author":"Fineschi","year":"2025","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1085742","article-title":"CD83 expressed by macrophages is an important immune checkpoint molecule for the resolution of inflammation","volume":"14","author":"Peckert-Maier","year":"2023","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13926","article-title":"Innate immune activation is a strong suppressor of CCL22 and impedes regulatory T cell-dendritic cell interaction","author":"Piseddu","year":"2025","journal-title":"Immunology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.10.7243","article-title":"Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis","volume":"181","author":"Mozaffarian","year":"2008","journal-title":"J Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/03008207.2018.1500558","article-title":"Oncostatin M and its role in fibrosis","volume":"60","author":"Stawski","year":"2019","journal-title":"Connect Tissue Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1165\/rcmb.2021-0358OC","article-title":"Tissue proteomic analysis identifies mechanisms and stages of immunopathology in fatal COVID-19","volume":"66","author":"Russell","year":"2022","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2023.1085988","article-title":"Biomarkers in long COVID-19: A systematic review","volume":"10","author":"Lai","year":"2023","journal-title":"Front Med (Lausanne)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1186\/s12879-023-08294-w","article-title":"Elevated interleukin (IL)-6 as a predictor of disease severity among Covid-19 patients: a prospective cohort study","volume":"23","author":"Nikkhoo","year":"2023","journal-title":"BMC Infect Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.019","article-title":"Epigenetic memory of coronavirus infection in innate immune cells and their progenitors","volume":"186","author":"Cheong","year":"2023","journal-title":"Cell"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021731","article-title":"Can baseline IL-6 levels predict long COVID in subjects hospitalized for SARS-coV-2 disease","volume":"24","author":"Giannitrapani","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B36","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s40249-023-01086-z","article-title":"Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis","volume":"12","author":"Yin","year":"2023","journal-title":"Infect Dis Poverty"},{"key":"B37","doi-asserted-by":"publisher","first-page":"131:105295","DOI":"10.1016\/j.psyneuen.2021.105295","article-title":"Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19","author":"Kappelmann","year":"2021","journal-title":"Psychoneuroendocrinology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae031","article-title":"Interleukin-1 receptor antagonist gene (IL1RN) variants modulate the cytokine release syndrome and mortality of COVID-19","volume":"229","author":"Attur","year":"2024","journal-title":"J Infect Dis"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e177123","DOI":"10.1172\/JCI177123","article-title":"Angiopoietin-like protein 2 mediates vasculopathy-driven fibrogenesis in a mouse model of systemic sclerosis","volume":"135","author":"Saha","year":"2025","journal-title":"J Clin Invest"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e70370","DOI":"10.1111\/acel.70370","article-title":"Context-dependent roles of ANGPTL2-mediated inflammaging in tissue homeostasis, pathological tissue remodeling, and longevity","volume":"25","author":"Yumoto","year":"2026","journal-title":"Aging Cell"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/cimb47050357","article-title":"The mechanisms of chronic inflammation in obesity and potential therapeutic strategies: A narrative review","volume":"47","author":"Gkrinia","year":"2025","journal-title":"Curr Issues Mol Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14041086","article-title":"Serum spike protein persistence post COVID is not associated with ME\/CFS","volume":"14","author":"Fehrer","year":"2025","journal-title":"J Clin Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1775044\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T06:30:40Z","timestamp":1771828240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1775044\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2026.1775044"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1775044","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]},"article-number":"1775044"}}