Tag: long covid immunology

Plasma proteomic profile reveals persistent immune activation in post-acute sequelae of SARS-CoV-2 infection

Abstract:

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.

Source: Fineschi S, Klar J, Schuster J, Bergquist J and Dahl N (2026) Plasma proteomic profile reveals persistent immune activation in post-acute sequelae of SARS-CoV-2 infection. Front. Immunol. 17:1775044. doi: 10.3389/fimmu.2026.1775044  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1775044/full (Full text)

Activation of the Lectin Pathway Drives Persistent Complement Dysregulation in Long COVID

Abstract:

Long COVID affects a substantial proportion of survivors of acute infection with severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), who suffer a variety of symptoms that limit their quality of life and economic activity. Although the aetiology of long COVID is obscure, it appears to be a chronic inflammatory condition. Complement dysregulation is a prevalent feature of long COVID. Specifically, markers of classical, alternative, and terminal pathway activation are often elevated in patients with this condition.

Here, we used a sensitive assay for mannan-binding lectin-associated serine protease-2 (MASP-2)/C1Inh complexes to analyse lectin pathway activation in a previously characterised cohort of patients with long COVID (n = 159) and healthy convalescent individuals with no persistent symptoms after infection with SARS-CoV-2 (n = 76). The data were combined with those from the most predictive complement analytes identified previously to delineate potential biomarkers of long COVID. MASP-2/C1Inh complexes were significantly elevated in patients with long COVID (p = 0.0003). Generalised linear modelling further identified an optimal set of four markers, namely iC3b (alternative pathway), TCC (terminal pathway), MASP-2/C1Inh (lectin pathway), and the complement regulator properdin, which had a receiver operating characteristic predictive power of 0.796 (95% confidence interval = 0.664-0.905). Combinations of the classical pathway markers C4, C1q, and C1s/C1Inh were poorly predictive of long COVID.

These findings demonstrate that activation of the lectin complement pathway, which occurs upstream of the alternative and terminal pathways and can be inhibited therapeutically, is a salient feature of long COVID.

Source: Keat SBK, Khatri P, Ali YM, Arachchilage CH, Demopulos G, Baillie K, Miners KL, Ladell K, Jones SA, Davies HE, Price DA, Zelek WM, Morgan BP, Schwaeble WJ, Lynch NJ. Activation of the Lectin Pathway Drives Persistent Complement Dysregulation in Long COVID. Immunology. 2026 Jan 25. doi: 10.1111/imm.70110. Epub ahead of print. PMID: 41581925. https://onlinelibrary.wiley.com/doi/10.1111/imm.70110?af=R (Full text)

Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID

Abstract:

Background: Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with SARS-CoV-2. The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID.

Methods: We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/sex/infection/vaccine-matched patients with long COVID.

Findings: Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785.

Conclusions: These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID.

Source:Baillie K, Davies HE, Keat SBK, Ladell K, Miners KL, Jones SA, Mellou E, Toonen EJM, Price DA, Morgan BP, Zelek WM. Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID. Med. 2024 Mar 8;5(3):239-253.e5. doi: 10.1016/j.medj.2024.01.011. Epub 2024 Feb 15. PMID: 38359836. https://www.sciencedirect.com/science/article/pii/S2666634024000412 (Full text)

Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers

Abstract:

Background: Postacute sequelae of COVID-19 (PASC), also known as long COVID, and postacute COVID-19 vaccination syndrome (PACVS) present overlapping but distinct clinical challenges. We hypothesize that PASC and PACVS share clinical features but differ in symptom patterns and biomarker profiles. This study aims to identify differences in presentation and distinguish immunologic biomarkers relevant to general clinical practice.

Methods: This cross-sectional study analyzed 181 patients from a PASC clinic at Columbia University Irving Medical Center. Patients were divided into PASC with myalgic encephalomyelitis/chronic fatigue syndrome (MECFS), PASC without MECFS (LC), and PACVS groups. Prevalence and severity of self-reported symptoms, as well as immunologic abnormalities, were compared across groups.

Results: Fatigue was the most common symptom (Total: 88.95%; MECFS: 100.00%; PACVS: 92.86%; LC: 78.05%). The MECFS group generally reported more symptoms across all organ systems. The PACVS group reported higher rates of atypical chief complaints such as peripheral neuropathy (17.9%), tinnitus (7.1%), and rash (10.7%) compared to the other groups (P = <.01). Functional impairment was comparable between the MECFS and PACVS groups and less severe in the LC group. All groups had high rates of autoantibody positivity and cytokine elevation. The PACVS group showed significantly higher rates of anticardiolipin IgM (PACVS 42.9%, LC 11.6%; P = .02) and anti-U1-RNP (PACVS 21.4%, LC 2.3%; P = .04) positivity compared to the LC group.

Conclusions: PASC and PACVS share symptom overlap but exhibit distinct biomarker patterns, particularly elevated autoantibody levels in PACVS. These findings suggest autoimmune involvement, warranting further investigation for targeted therapies.

Source: Purpura L, Heisler T, Palmer S, Shah J, Graham A, Seo GY, Sturiza A, Javier X, Pinto G, Rosa A, Bosco J, Reis K, Sobieszczyk ME, Yin MT. Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers. Clin Infect Dis. 2026 Jan 9:ciaf624. doi: 10.1093/cid/ciaf624. Epub ahead of print. PMID: 41510565. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf624/8417802 (Full text)

Post-translational modifications within fibrinaloid microclot complexes distinguish Pre-COVID-19 Postural Orthostatic Tachycardia Syndrome, Long COVID, and Long COVID-POTS and reveal disease-specific molecular pathways

Abstract:

Background: Pre-COVID-19 Postural orthostatic tachycardia syndrome (PC-POTS), Long COVID, and their overlap (LC-POTS) are chronic post-viral conditions marked by debilitating symptoms despite frequently normal routine laboratory results. We have previously identified insoluble fibrinaloid microclot complexes (FMCs) in Long COVID. It is not known whether FMCs are also present in PC-POTS, or whether post-translational modifications (PTMs) within FMC-entrapped proteins contribute to disease mechanisms.

Methods: Platelet-poor plasma from healthy controls, PC-POTS patients (collected prior to the COVID-19 pandemic), Long COVID (without POTS) and LC-POTS patients underwent fluorescence imaging flow cytometry to quantify FMCs. Proteomic analyses were performed on insoluble protein fractions using a double trypsin digestion strategy and data-independent liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differential protein abundance, PTMs, and amyloidogenicity were compared across groups.

Results: Measured with imaging flow cytometry in objects/mL, higher levels of FMCs were present in disease groups compared to controls, although not statistically significant. Statistically significant differences potentially lay within FMC sizes and composition. Furthermore, despite only a few dysregulated proteins, FMC proteomics revealed extensive and disease-specific peptides with PTM dysregulation across coagulation, immune, and metabolic pathways. Long COVID displayed FMCs with PTMs of coagulation proteins including prominent advanced glycation end-products (AGE)- and oxidation-based modifications of fibrinogen subunits, particularly fibrinogen subunit A (FIBA), resembling diabetic glycation profiles. FMCs in PC-POTS showed fewer fibrinogen PTMs but markedly increased modifications in metabolic proteins, including oxidised apoA1 and apoB, and immune patterns with complement-related proteins (C3, C4A/B, IC1), immunoglobulin G1 (IGG1) and alpha 2 macroglobulin (A2MG). LC-POTS shared coagulation pathology with Long COVID and immune pathology with PC-POTS. Many dysregulated peptides were determined by in silco methods to be highly amyloidogenic, consistent with FMCs as beta-sheet-rich aggregates. Protein-level differences were minimal compared with PTM changes.

Conclusions: This study provides the first evidence that post-translational modifications (PTMs) within fibrinaloid microclots complexes (FMCs) uniquely distinguish pre-COVID-19 POTS, Long COVID, and Long COVID-POTS. Because PC-POTS samples were collected before SARS-CoV-2, their PTM patterns reflect intrinsic disease biology, allowing a clear separation from Long COVID-related changes. PTM profiling revealed pro-coagulant fibrinogen modifications in Long COVID and LC-POTS, metabolic-oxidative disruptions in Long COVID and PC-POTS, and immune dysregulation in PC-POTS and LC-POTS. None of these is detectable with routine assays, and all are independent of protein abundance. The consistent presence of amyloidogenic peptides suggests a contribution to microvascular dysfunction. These findings define disease-specific PTM landscapes and support new diagnostic and therapeutic avenues across autonomic and post-viral disorders.

Source: Renata Madre Booyens, Mare Vlok, Cecile Bester, Rashmin Hira, M Asad Khan, Douglas B Kell, Satish R Raj, Etheresia Pretorius. Post-translational modifications within fibrinaloid microclot complexes distinguish Pre-COVID-19 Postural Orthostatic Tachycardia Syndrome, Long COVID, and Long COVID-POTS and reveal disease-specific molecular pathways.
bioRxiv 2025.12.29.696828; doi: https://doi.org/10.64898/2025.12.29.696828 https://www.biorxiv.org/content/10.64898/2025.12.29.696828v1 (Full text available as PDF file)

Comparable Immune Alterations and Inflammatory Signatures in ME/CFS and Long COVID

Abstract:

Background: Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), is a debilitating condition characterized by persistent fatigue and multisystemic symptoms, such as cognitive impairment, musculoskeletal pain, and post-exertional malaise. Recently, parallels have been drawn between ME/CFS and Long COVID, a post-viral syndrome following infection with SARS-CoV-2, which shares many clinical features with CFS. Both conditions involve chronic immune activation, raising questions about their immunopathological overlap.

Objectives: This study aimed to compare immune biomarkers between patients with ME/CFS or Long COVID and healthy controls to explore shared immune dysfunction.

Methods: We analyzed lymphocyte subsets, cytokine profiles, psychological status and their correlations in 190 participants, 65 with CFS, 54 with Long COVID, and 70 healthy controls.

Results: When compared to healthy subjects, results in both conditions were marked by lower levels of lymphocytes (CFS-2.472 × 109/L, p = 0.006, LC-2.051 × 109/L, p = 0.009), CD8+ T cells (CFS-0.394 × 109/L, p = 0.001, LC-0.404 × 109/L, p = 0.001), and NK cells (CFS-0.205 × 109/L, p = 0.001, LC-0.180 × 109/L, p = 0.001), and higher levels of proinflammatory cytokines such as IL-6 (CFS-3.35 pg/mL, p = 0.050 LC-4.04 pg/mL, p = 0.001), TNF (CFS-2.64 pg/mL, p = 0.023, LC-2.50 pg/mL, p = 0.025), IL-4 (CFS-3.72 pg/mL, p = 0.041, LC-3.45 pg/mL, p = 0.048), and IL-10 (CFS-2.29 pg/mL, p = 0.039, LC-2.25 pg/mL, p = 0.018).

Conclusions: Notably, there were no significant differences between CFS and Long COVID patients in the tested biomarkers. These results demonstrate that ME/CFS and Long COVID display comparable immune and inflammatory profiles, with no significant biomarker differences observed between the two groups.

Source: Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Dudova D, Nikolova R, Vaseva K, Todorova Y, Aleksova M, Nikolova M, Taskov H, Murdjeva M, Maes M. Comparable Immune Alterations and Inflammatory Signatures in ME/CFS and Long COVID. Biomedicines. 2025 Dec 8;13(12):3001. doi: 10.3390/biomedicines13123001. PMID: 41463013. https://www.mdpi.com/2227-9059/13/12/3001 (Full text)

Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS

Abstract:

Long COVID (LC) manifests with sex-specific differences, particularly in those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study reveals that female LC patients (LCF) with ME/CFS show a shift toward myelopoiesis, reduced lymphocytes, increased neutrophils/monocytes, and depleted regulatory T cells-suggesting persistent immune activation. Elevated CD71+ erythroid cells and disrupted erythropoiesis contribute to fatigue and tissue damage in LCF.

Cytokine profiling indicates a stronger pro-inflammatory response in LCF compared to males (LCM), along with markers of gut barrier dysfunction. Hormonal analysis shows reduced testosterone in LCF and estradiol in LCM. Transcriptomic data reveal neuroinflammatory signatures in LCF, potentially explaining cognitive symptoms. We also identify biomarkers that distinguish LCF from LCM and correlate with sex-specific clinical symptoms.

Overall, LC with ME/CFS is characterized by sex-specific immune, hormonal, and transcriptional alterations, with females exhibiting more severe inflammation. These insights underscore the need for sex-tailored interventions, including consideration of hormone replacement therapy.

Source: Shahbaz S, Osman M, Syed H, Mason A, Rosychuk RJ, Cohen Tervaert JW, Elahi S. Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS. Cell Rep Med. 2025 Nov 7:102449. doi: 10.1016/j.xcrm.2025.102449. Epub ahead of print. PMID: 41205594. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00522-1 (Full text)

Cytokine profiles associated with persisting symptoms of post-acute sequelae of COVID-19

Abstract:

Background/aims: Post-acute sequelae of COVID-19 (PASC) are highly heterogeneous; therefore, the pathophysiological mechanisms for PASC remain unclear. In this study, we aimed to examine the immunologic aspects of various PASC symptoms.

Methods: We prospectively enrolled adults aged ≥ 18 years who were diagnosed with COVID-19 between August 2022 and September 2023. Blood samples were collected from all participants, who were interviewed using a questionnaire for PASC symptoms at least once between 1 and 6 months after the COVID-19 diagnosis. For immunological evaluation, plasma concentrations of SARS-CoV-2 spike subunit 1-specific IgG and 33 cytokines were measured using enzyme-linked immunosorbent assays and multiplex-based immunoassay, respectively.

Results: In total, 156 pairs of blood samples and symptom reports from 79 participants were eligible for analysis. The most frequent symptom was fatigue, followed by post exertional malaise, chronic cough, thirst, and brain fog. Gastrointestinal symptoms, chest pain, post exertional malaise, smell/taste change, fatigue, brain fog, abnormal movement, and palpitation were accompanied by significant increases in IL-10, VEGF, and inflammatory cytokines like MIP-1α, IL-1β, IL-6, IL-8, MIG, granzyme A, and CX3CL1 levels, while chronic cough, dizziness, dyspnea, and hair loss were not accompanied by significant differences in cytokine levels.

Conclusion: Symptoms classified into different categories based on the dysfunctional organs may share a common pathophysiology regarding elevation of certain cytokines. Although PASC symptoms are heterogeneous, our findings suggest that T-cell recruitment, thrombosis, and increased vascular permeability might contribute to various symptom clusters sharing common pathophysiological mechanisms.

Source: Kwon JS, Chang E, Jang HM, Kim JY, Kim W, Son JY, Cha J, Jang CY, Bae S, Jung J, Kim MJ, Chong YP, Lee SO, Choi SH, Kim YS, Kim SH. Cytokine profiles associated with persisting symptoms of post-acute sequelae of COVID-19. Korean J Intern Med. 2025 Jul;40(4):667-675. doi: 10.3904/kjim.2024.217. Epub 2025 Jul 1. PMID: 40635493. https://kjim.org/journal/view.php?doi=10.3904/kjim.2024.217 (Full text)

Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection

Abstract:

SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood.

In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58).

Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC.

Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.

Source: Lage SL, Bricker-Holt K, Rocco JM, Rupert A, Donovan FX, Abramzon YA, Chandrasekharappa SC, McNinch C, Cook L, Amaral EP, Rosenfeld G, Dalhuisen T, Eun A, Hoh R, Fehrman E, Martin JN, Deeks SG, Henrich TJ, Peluso MJ, Sereti I. Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection. medRxiv [Preprint]. 2025 Apr 17:2025.04.16.25325949. doi: 10.1101/2025.04.16.25325949. PMID: 40321289; PMCID: PMC12047922. https://pmc.ncbi.nlm.nih.gov/articles/PMC12047922/ (Full text)

Long COVID-19 autoantibodies and their potential effect on fertility

Abstract:

Impaired spermatogenesis has been reported in coronavirus disease 2019 (COVID-19) patients. However, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on male fertility remains unclear. The purpose of this multicenter study was to investigate the possible impact of SARS-CoV-2 infection on male fertility and determine the potential reasons leading to impaired male reproductive functions.

In silico approach identified ~60 amino acid sequences containing at least five continuous residues shared by SARS-CoV-2 Spike glycoprotein and spermatogenesis-linked proteins. Four synthetic peptides were tested with sera from independent cohorts of patients with acute and long COVID-19 syndrome (LCS), and naïve vaccinated subjects. Immunogenicity and pathogenicity studies were performed by immunizing mice with two selected peptides and testing the antigenicity of induced antibodies.

While none of four peptides were recognized by antibodies from vaccinated people, infected patients exhibited high reactivity to peptide 4, and LCS patients, especially women, showed elevated antibody levels against peptide 2. Women with LCS and chronic fatigue syndrome had higher levels of peptide 2-reacting antibodies than those with idiopathic chronic fatigue syndrome. Noteworthy, peptide 2 antibodies showed, in in vitro experiment, a specific interaction with mouse testicular tissue antigens.

These findings raise the possibility that cross-reactive epitopes between SARS-CoV-2 Spike protein and spermatogenesis-related antigens may affect infected patients’ fertility, suggesting a potential for autoimmune responses with human consequences.

Source: Talamini L, Fonseca DLM, Kanduc D, Chaloin O, Verdot C, Galmiche C, Dotan A, Filgueiras IS, Borghi MO, Meroni PL, Gavrilova NY, Ryabkova VA, Churilov LP, Halpert G, Lensch C, Thurner L, Fong SW, Ng LFP, Rénia L, Young BE, Lye DC, Lozano JM, Cabral-Marques O, Shoenfeld Y, Muller S. Long COVID-19 autoantibodies and their potential effect on fertility. Front Immunol. 2025 May 27;16:1540341. doi: 10.3389/fimmu.2025.1540341. PMID: 40496870; PMCID: PMC12149208.  https://pmc.ncbi.nlm.nih.gov/articles/PMC12149208/ (Full text)