Tag: long covid pathomechanism

SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19

Abstract:

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production.

The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression.

These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

Source: Guarnieri JW, Haltom JA, Albrecht YES, Lie T, Olali AZ, Widjaja GA, Ranshing SS, Angelin A, Murdock D, Wallace DC. SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19. Pharmacol Res. 2024 Apr 11:107170. doi: 10.1016/j.phrs.2024.107170. Epub ahead of print. PMID: 38614374. https://www.sciencedirect.com/science/article/pii/S1043661824001142 (Full text)

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

Abstract:

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered.

Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms.

Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms.

Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Source: Liew F, Efstathiou C, Fontanella S, Richardson M, Saunders R, Swieboda D, Sidhu JK, Ascough S, Moore SC, Mohamed N, Nunag J, King C, Leavy OC, Elneima O, McAuley HJC, Shikotra A, Singapuri A, Sereno M, Harris VC, Houchen-Wolloff L, Greening NJ, Lone NI, Thorpe M, Thompson AAR, Rowland-Jones SL, Docherty AB, Chalmers JD, Ho LP, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard LS, Wootton DG, Quint JK, de Silva TI, Ho A, Chiu C, Harrison EM, Greenhalf W, Baillie JK, Semple MG, Turtle L, Evans RA, Wain LV, Brightling C, Thwaites RS, Openshaw PJM; PHOSP-COVID collaborative group; ISARIC investigators. Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease. Nat Immunol. 2024 Apr;25(4):607-621. doi: 10.1038/s41590-024-01778-0. Epub 2024 Apr 8. PMID: 38589621; PMCID: PMC11003868. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11003868/ (Full text)

Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach

Abstract:

Despite the recent and increasing knowledge surrounding COVID-19 infection, the underlying mechanisms of the persistence of symptoms for a long time after the acute infection are still not completely understood. Here, a multiplatform mass spectrometry-based approach was used for metabolomic and lipidomic profiling of human plasma samples from Long COVID patients (n = 40) to reveal mitochondrial dysfunction when compared with individuals fully recovered from acute mild COVID-19 (n = 40).

Untargeted metabolomic analysis using CE-ESI(+/-)-TOF-MS and GC-Q-MS was performed. Additionally, a lipidomic analysis using LC-ESI(+/-)-QTOF-MS based on an in-house library revealed 447 lipid species identified with a high confidence annotation level. The integration of complementary analytical platforms has allowed a comprehensive metabolic and lipidomic characterization of plasma alterations in Long COVID disease that found 46 relevant metabolites which allowed to discriminate between Long COVID and fully recovered patients.

We report specific metabolites altered in Long COVID, mainly related to a decrease in the amino acid metabolism and ceramide plasma levels and an increase in the tricarboxylic acid (TCA) cycle, reinforcing the evidence of an impaired mitochondrial function. The most relevant alterations shown in this study will help to better understand the insights of Long COVID syndrome by providing a deeper knowledge of the metabolomic basis of the pathology.

Source: Martínez S, Albóniga OE, López-Huertas MR, Gradillas A, Barbas C. Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach. J Proteome Res. 2024 Apr 2. doi: 10.1021/acs.jproteome.3c00706. Epub ahead of print. PMID: 38566450. https://pubmed.ncbi.nlm.nih.gov/38566450/

Blood Markers Show Neural Consequences of LongCOVID-19

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system.
To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection.
IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43.
This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.
Source: Tang N, Kido T, Shi J, McCafferty E, Ford JM, Dal Bon K, Pulliam L. Blood Markers Show Neural Consequences of LongCOVID-19. Cells. 2024; 13(6):478. https://doi.org/10.3390/cells13060478 https://www.mdpi.com/2073-4409/13/6/478 (Full text)

Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19

Abstract:

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC.

A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1-3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes.

Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

Source: Hanson AL, Mulè MP, Ruffieux H, Mescia F, Bergamaschi L, Pelly VS, Turner L, Kotagiri P; Cambridge Institute of Therapeutic Immunology and Infectious Disease–National Institute for Health Research (CITIID–NIHR) COVID BioResource Collaboration; Göttgens B, Hess C, Gleadall N, Bradley JR, Nathan JA, Lyons PA, Drakesmith H, Smith KGC. Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Nat Immunol. 2024 Mar;25(3):471-482. doi: 10.1038/s41590-024-01754-8. Epub 2024 Mar 1. PMID: 38429458; PMCID: PMC10907301. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10907301/ (Full text)

Unraveling Links between Chronic Inflammation and Long COVID: Workshop Report

As COVID-19 continues, an increasing number of patients develop long COVID symptoms varying in severity that last for weeks, months, or longer. Symptoms commonly include lingering loss of smell and taste, hearing loss, extreme fatigue, and “brain fog.” Still, persistent cardiovascular and respiratory problems, muscle weakness, and neurologic issues have also been documented. A major problem is the lack of clear guidelines for diagnosing long COVID. Although some studies suggest that long COVID is due to prolonged inflammation after SARS-CoV-2 infection, the underlying mechanisms remain unclear.

The broad range of COVID-19’s bodily effects and responses after initial viral infection are also poorly understood. This workshop brought together multidisciplinary experts to showcase and discuss the latest research on long COVID and chronic inflammation that might be associated with the persistent sequelae following COVID-19 infection.

Source: Pushpa Tandon, Natalie D. Abrams, Leela Rani Avula, Danielle M. Carrick, Preethi Chander, Rao L. Divi, Johanna T. Dwyer, Gallya Gannot, Nataliya Gordiyenko, Qian Liu, Kyung Moon, Mercy PrabhuDas, Anju Singh, Mulualem E. Tilahun, Merriline M. Satyamitra, Chiayeng Wang, Ronald Warren, Christina H. Liu; Unraveling Links between Chronic Inflammation and Long COVID: Workshop Report. J Immunol 15 February 2024; 212 (4): 505–512. https://doi.org/10.4049/jimmunol.2300804 https://journals.aai.org/jimmunol/article/212/4/505/266648 (Full text)

Long Covid

Abstract:

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), refers to a constellation of persistent symptoms and health issues that continue beyond the acute phase of COVID-19. This chapter provides an overview of the pathogenesis, risk factors, manifestations, major findings, and diagnosis and treatment strategies associated with Long COVID.

Hypotheses regarding the pathogenesis of Long COVID are discussed, encompassing various factors such as persistent viral reservoirs, immune dysregulation with or without reactivation of herpesviruses (e.g., Epstein-Barr Virus and human herpesvirus), dysbiosis, autoimmunity triggered by infection, endothelial dysfunction, microvessel blood clotting, and dysfunctional brainstem and/or vagal signaling. The chapter also highlights the risk factors associated with Long COVID and its occurrence in children.

The major findings of Long COVID, including immune dysregulation, vessel and tissue damage, neurological and cognitive pathology, eye symptoms, endocrinal issues, myalgic encephalomyelitis and chronic fatigue syndrome, reproductive system involvement, respiratory and gastrointestinal symptoms, and the chronology of symptoms, are thoroughly explored.

Lastly, the chapter discusses the challenges and current approaches in the diagnosis and treatment of Long COVID, emphasizing the need for multidisciplinary care and individualized management strategies.

Source: Asiya Kamber Zaidi and Puya Dehgani-Mobaraki. Long Covid. Progress in Molecular Biology and Translational Science, Volume 202, 2024, Pages 113-125 https://www.sciencedirect.com/science/article/abs/pii/S1877117323001771

Repeated Hand Grip Strength is an Objective Marker for Disability and Severity of Key Symptoms in Post-COVID ME/CFS

Abstract:

Post-COVID Syndrome (PCS) refers to a diverse array of symptoms that persist beyond 3 months of the acute phase of a SARS-CoV-2 infection. The most frequent symptom is fatigue, which can manifest both mentally and physically. In this study, handgrip strength (HGS) parameters were determined as an objective measure of muscle fatigue and fatigability. HGS parameters were correlated with other frequent symptoms among 144 female PCS patients suffering from fatigue, exertional intolerance, and cognitive impairment.

Seventy-eight patients met the Canadian Consensus Criteria (CCC) for post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The severity of disability and key symptoms were evaluated utilizing self-reported questionnaires.

Notably, patients diagnosed with ME/CFS exhibited a higher overall severity of symptoms, including lower physical function (p < 0.001), a greater degree of disability (p < 0.001), more severe fatigue (p < 0.001), post-exertional malaise (p < 0.001), and autonomic dysfunction (p = 0.004). While HGS was similarly impaired in both PCS and ME/CFS patients, the associations between HGS and the severity of symptoms and disability revealed striking differences.

We observed significant correlations of HGS parameters with physical function across all patients, but with the key symptoms PEM, fatigue, cognitive impairment, and autonomic dysfunction in ME/CFS patients only. This points to a common mechanism for these symptoms in the ME/CFS subtype, distinct from that in other types of PCS. Further HGS provides an objective marker of disease severity in ME/CFS.

Source: Anna Paffrath, Laura Kim, Claudia Kedor, Elisa Stein, Rebekka Rust, Helma Freitag, Uta Hoppmann, Leif G Hanitsch, Judith Bellmann-Strobl, Kirsten Wittke, Carmen Scheibenbogen, Franziska Sotzny. Repeated Hand Grip Strength is an Objective Marker for Disability and Severity of Key Symptoms in Post-COVID ME/CFS.
medRxiv 2024.01.25.24301776;  https://www.medrxiv.org/content/10.1101/2024.01.25.24301776v1 (Full text available as PDF file)

Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients

Abstract:

Background: Long COVID symptoms are widely diffused and have a poorly understood pathophysiology, with possible involvement of inflammatory cytokines.

Materials and methods: A prospective follow-up study involved 385 unvaccinated patients, started 1 month after SARS-CoV-2 infection and continued for up to 12 months. We compared circulating biomarkers of neutrophil degranulation, endothelial and metabolic dysfunction in subjects with long COVID symptoms and in asymptomatic post-COVID controls.

Results: The highest occurrence of symptoms (71%) was after 3 months from the infection, decreasing to 62.3% and 29.4% at 6 and 12 months, respectively. Compared to controls, long COVID patients had increased levels of the neutrophilic degranulation indices MMP-8 and MPO, of endothelial dysfunction indices L-selectin and P-selectin. Among indices of metabolic dysfunction, leptin levels were higher in long COVID patients than in controls.

Conclusion: In unvaccinated patients, symptoms may persist up to 1 year after acute COVID infection, with increased indices of neutrophil degranulation, endothelial and metabolic dysfunction. The clinical implications of specific inflammatory biomarkers require further attention, especially in individuals with fatigue and long COVID-linked cognitive dysfunctions.

Source: Di Ciaula A, Liberale L, Portincasa P, Khalil M, Galerati I, Farella I, Noto A, JohnBritto S, Moriero M, Michelauz C, Frè F, Olivero C, Bertolotto M, Montecucco F, Carbone F, Bonfrate L. Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients. Eur J Clin Invest. 2024 Jan 16:e14155. doi: 10.1111/eci.14155. Epub ahead of print. PMID: 38226472. https://pubmed.ncbi.nlm.nih.gov/38226472/

THE ROLE OF α7 NICOTINIC ACETYLCHOLINE RECEPTORS IN POST-ACUTE SEQUELAE OF COVID-19

Abstract:

Post-Acute Sequelae of COVID-19 or Long COVID becomes evident some weeks to months following acute COVID-19. Symptoms include cognitive impairment and varying degrees of memory loss with no definitive etiologies or efficacious therapies forthcoming even after four years of the SARS-Cov2 pandemic virus. The aim of this review is to demonstrate the important role of α7 nicotinic acetylcholine receptors in both acute COVID-19 and Long COVID.

Evidence presented implicates immune mechanisms stimulated by SARS-Cov-2 S-protein fragment 674-685 that possesses homology with α7-specific ligands. Cognitive dysfunctions observed in Long COVID patients may be derived from anti-idiotypic α7-specific antibodies stimulated by (674-685)-specific antibodies. Therapeutic interventions capable of neutralizing these antibodies and restoring full functions of α7 nicotinic acetylcholine receptors appear to be of paramount importance in post-acute sequelae of COVID-19.

Source: Skok M. THE ROLE OF α7 NICOTINIC ACETYLCHOLINE RECEPTORS IN POST-ACUTE SEQUELAE OF COVID-19. Int J Biochem Cell Biol. 2024 Jan 11:106519. doi: 10.1016/j.biocel.2024.106519. Epub ahead of print. PMID: 38218363. https://www.sciencedirect.com/science/article/abs/pii/S1357272524000104