Tag: long covid pathomechanism

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)

Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms.

The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.

The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue.

Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Source: Nunes M, Kell L, Slaghekke A, Wüst RC, Fielding BC, Kell DB, Pretorius E. Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system. Cell Death Dis. 2026 Jan 9;17(1):16. doi: 10.1038/s41419-025-08162-2. PMID: 41513611; PMCID: PMC12789617. https://pmc.ncbi.nlm.nih.gov/articles/PMC12789617/ (Full text)

Differential Characteristics and Comparison Between Long-COVID Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Long-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome are disabling diseases characterised by ongoing fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome typically follows viral infections, whereas Long-COVID exclusively follows SARS-CoV-2 infection, with overlapping but distinct features. This review uses comprehensive searches of online databases to compare their clinical presentations, pathophysiologies, and treatments.

Both Long-COVID and ME/CFS appear to involve multifactorial mechanisms, including viral persistence, immune dysregulation, endothelial dysfunction, and autoimmunity, though their relative contributions remain uncertain. Symptom management strategies are consistent, however. Cognitive behaviour therapy has been successful, and there are minimal drug treatments. Graded exercise therapy occupies a contested place, recommending individualised pacing and multidisciplinary rehabilitation.

Common and exclusive mechanisms must be identified to formulate valuable therapies. A more significant body of research focusing on immune dysfunction as a pathogenic mechanism for advancing the disease and enabling more effective therapies and diagnostics is needed.

Source: Ivanovska M, Homadi MS, Angelova G, Taskov H, Murdjeva M. Differential Characteristics and Comparison Between Long-COVID Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Biomedicines. 2025 Nov 17;13(11):2797. doi: 10.3390/biomedicines13112797. PMID: 41301889; PMCID: PMC12650534. https://pmc.ncbi.nlm.nih.gov/articles/PMC12650534/ (Full text)

Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies

Abstract:

Although Gulf War Illness (GWI), fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID have distinct origins, in this article we have reviewed evidence that these disorders comprise a group of so-called low-energy associated disorders with overlapping common symptoms underlying pathology.

In particular, evidence for mitochondrial dysfunction, oxidative stress, inflammation, immune dysregulation, neuroendocrine dysfunction, disrupted brain-gut-microbiome axis, apoptosis/ferroptosis and telomere shortening as common features in the pathogenesis of these disorders has been identified.

Given the role of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, as an antioxidant, antiinflammatory and antiapoptotic and antiferroptotic agent, there is a rationale for supplementary CoQ10 in the management of these disorders. The reported benefits of supplementary CoQ10 administration in GWI, FM, ME/CFS and long COVID have been reviewed; the potential benefit of supplementary CoQ10 in reducing telomere shortening and improving the efficiency of stem cell transfer relevant has also been identified as promising therapeutic strategies in these disorders.

This review advances beyond previous systematic reviews and consensus statements on overlapping similar symptoms and underlying biological pathomechanisms in these complex disorders.

Source: Mantle D, Domingo JC, Golomb BA, Castro-Marrero J. Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies. Int J Mol Sci. 2025 Sep 17;26(18):9044. doi: 10.3390/ijms26189044. PMID: 41009608. https://www.mdpi.com/1422-0067/26/18/9044 (Full text)

Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID are complex, disabling conditions that have emerged as significant public health challenges, affecting millions worldwide. Despite their growing prevalence, effective diagnostics and treatments remain limited, largely due to an incomplete understanding of their underlying pathophysiology. Both conditions share hallmark symptoms of chronic fatigue, cognitive dysfunction, and postexertional malaise, but their biological underpinnings remain to be elucidated. Neuroimaging offers a promising, noninvasive window into the brain’s metabolic landscape and has the potential to uncover objective biomarkers for these conditions.

In this mini review, we highlight recent advancements in metabolic neuroimaging, particularly positron emission tomography and magnetic resonance imaging/magnetic resonance spectroscopy, that reveal alterations in glucose and oxygen metabolism, neurotransmitter balance, and oxidative stress. These insights point toward shared disruptions in brain energy metabolism and neuroinflammatory processes, which may underlie the persistent symptoms in both ME/CFS and Long-COVID.

Importantly, while some findings overlap, inconsistencies in metabolite profiles between ME/CFS and Long-COVID underscore the need for further stratification and longitudinal research. Standardizing definitions, such as identifying Long-COVID patients who meet ME/CFS diagnostic criteria, could help improve study comparability.

By summarizing current imaging evidence, this review underscores the potential of neuroimaging to identify imaging biomarkers to advance the clinical diagnosis of Long-COVID and identify therapeutic targets for treatment development. As we continue to face the growing burden of Long-COVID and ME/CFS, metabolic imaging may serve as a powerful tool to bridge gaps in knowledge and accelerate progress toward effective care.

Source: Zhu Y, Quan P, Yamazaki T, Norweg A, Natelson B, Xu X. Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID. Immunometabolism (Cobham). 2025 Sep 12;7(4):e00068. doi: 10.1097/IN9.0000000000000068. PMID: 40958852; PMCID: PMC12435251. https://pmc.ncbi.nlm.nih.gov/articles/PMC12435251/ (Full text)

A multi-omics recovery factor predicts long COVID in the IMPACC study

Abstract:

Background. Following SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which debilitating symptoms persist for at least three months. Elucidating biologic underpinnings of LC could identify therapeutic opportunities.

Methods. We utilized machine learning methods on biologic analytes provided over 12-months after hospital discharge from >500 COVID-19 patients in the IMPACC cohort to identify a multi-omics “recovery factor”, trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood CyTOF protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.

Results. LC participants had lower recovery factor scores compared to recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.

Conclusion. The multi-omics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

Trial Registration. ClinicalTrials.gov NCT04378777.

Funding. This study was funded by NIH, NIAID and NSF.

Source: Gisela Gabernet, Leying Guan, Lauren I.R. Ehrlich, et al. A multi-omics recovery factor predicts long COVID in the IMPACC study. J Clin Invest. September 9, 2025. https://doi.org/10.1172/JCI193698. https://www.jci.org/articles/view/193698/ (Full study available as PDF file)

Mitochondrial function is impaired in long COVID patients

Abstract:

Background: The Long COVID syndrome is a major global health problem, affecting approximately 10–20% of individuals infected with SARS-CoV-2 virus with many remaining symptomatic beyond one year. Fatigue, reduced exercise tolerance and hyperlactataemia on minimal exertion have led to the suggestion of a bioenergetic defect. We hypothesised that mitochondrial dysfunction is a pathological feature in Long COVID cases and would correlate with clinical outcome.

Methods: This prospective, case-controlled, observational study recruited 27 participants with an established diagnosis of Long COVID syndrome from a single tertiary clinic together with 16 age-matched controls aged 25–65 years. Seahorse-based mitochondrial flux analysis and bioenergetics profile of isolated peripheral blood mononuclear cells (PBMCs) was performed and correlated with clinical phenotype.

Findings: Long COVID cases had an increased baseline and ATP-induced oxygen consumption rate with a significant attenuation in tetramethylrhodamine methyl ester perchlorate fluorescence response to oligomycin. Correlations were observed between mitochondrial function and autonomic health, quality of life and time from index infection. Sex-specific differences were also observed.

Interpretation: PBMCs from Long COVID subjects exhibit an exceptional and distinctive change in ATP synthase, as it contributes to the mitochondrial membrane potential rather than using it exclusively to generate ATP. The findings suggest that the enzyme runs both forward and reverse reactions, synthesising and hydrolysing ATP. The correlation of mitochondrial function with clinical phenotype in Long COVID may indicate a causal relationship and warrants further validation in larger scale studies.

Source: Macnaughtan, J., Chau, K. Y., Brennan, E., Toffoli, M., Spinazzola, A., Hillman, T., … Schapira, A. H. V. (2025). Mitochondrial function is impaired in long COVID patients. Annals of Medicine, 57(1). https://doi.org/10.1080/07853890.2025.2528167 https://www.tandfonline.com/doi/full/10.1080/07853890.2025.2528167 (Full text)

Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Debilitating symptoms for many years can follow acute COVID-19 (“long COVID”), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60-400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms.

In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats-sickness behavior and torpor-responses mediated by specific, recently discovered neural circuits. These neural circuits constitute a symptom-generating pathway, activated by neuroinflammation, which may be targeted by therapeutics to quell neuroinflammation.

Many factors cause the symptoms to become chronic, including persistent infectious agents (and/or their nucleic acids and antigens) and the fact that many of the underlying biological abnormalities reinforce each other, creating ongoing physiological vicious cycles.

Source:Komaroff AL, Dantzer R. Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Cell Rep Med. 2025 Jul 25:102259. doi: 10.1016/j.xcrm.2025.102259. Epub ahead of print. PMID: 40744021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00332-5 (Full text)

Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study

Abstract:

Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a common debilitating medical condition, whose main symptoms – fatigue, post-exertional malaise and cognitive dysfunction – are also present in many cases of long COVID. Magnetic resonance spectroscopy (MRS) allows the insight into their pathophysiology through exploration of a range of biochemicals putatively relevant to aetiological processes, in particular mitochondrial dysfunction and energy metabolism.

24 patients with ME/CFS, 25 patients with long COVID and 24 healthy controls (HC) underwent brain (pregenual and dorsal anterior cingulate cortex, respectively, pgACC and dACC) and calf muscle MRS scanning at 7 Tesla, followed by a computerised cognitive assessment. Compared to HC, ME/CFS patients had elevated levels of lactate in both pgACC and dACC, while long COVID patients had lowered levels of total choline in dACC. By contrast, skeletal muscle metabolites at rest did not significantly differ between the groups.

The changes in lactate in ME/CFS are consistent with the presence of energetic stress and mitochondrial dysfunction. A reduction in total choline in long COVID is of interest in the context of the recently reported association between blood clots and ‘brain fog’, and earlier animal studies showing that choline might prevent intravascular coagulation.

Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations, may differ. An important implication is that patients with ME/CFS and those with fatigue in the course of long COVID should not be studied as a single group, at least until the mechanisms are better understood.

Source: Godlewska BR, Sylvester AL, Emir UE, Sharpley AL, Clarke WT, Williams SR, Gonçalves AJ, Raman B, Valkovič L, Cowen PJ. Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study. Mol Psychiatry. 2025 Jul 12. doi: 10.1038/s41380-025-03108-8. Epub ahead of print. PMID: 40652046. https://www.nature.com/articles/s41380-025-03108-8 (Full text)