Tag: inflammatory pathways

Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19

Abstract:

SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes.

Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19.

Source: Rong Z, Mai H, Ebert G, Kapoor S, Puelles VG, Czogalla J, Hu S, Su J, Prtvar D, Singh I, Schädler J, Delbridge C, Steinke H, Frenzel H, Schmidt K, Braun C, Bruch G, Ruf V, Ali M, Sühs KW, Nemati M, Hopfner F, Ulukaya S, Jeridi D, Mistretta D, Caliskan ÖS, Wettengel JM, Cherif F, Kolabas ZI, Molbay M, Horvath I, Zhao S, Krahmer N, Yildirim AÖ, Ussar S, Herms J, Huber TB, Tahirovic S, Schwarzmaier SM, Plesnila N, Höglinger G, Ondruschka B, Bechmann I, Protzer U, Elsner M, Bhatia HS, Hellal F, Ertürk A. Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19. Cell Host Microbe. 2024 Nov 26:S1931-3128(24)00438-4. doi: 10.1016/j.chom.2024.11.007. Epub ahead of print. PMID: 39615487. https://www.sciencedirect.com/science/article/pii/S1931312824004384 (Full text)

Thrombophilia and Immune-Related Genetic Markers in Long COVID

Abstract:

Aiming to evaluate the role of ten functional polymorphisms in long COVID, involved in major inflammatory, immune response and thrombophilia pathways, a cross-sectional sample composed of 199 long COVID (LC) patients and a cohort composed of 79 COVID-19 patients whose follow-up by over six months did not reveal any evidence of long COVID (NLC) were investigated to detect genetic susceptibility to long COVID.
Ten functional polymorphisms located in thrombophilia-related and immune response genes were genotyped by real time PCR. In terms of clinical outcomes, LC patients presented higher prevalence of heart disease as preexistent comorbidity. In general, the proportions of symptoms in acute phase of the disease were higher among LC patients.
The genotype AA of the interferon gamma (IFNG) gene was observed in higher frequency among LC patients (60%; p = 0.033). Moreover, the genotype CC of the methylenetetrahydrofolate reductase (MTHFR) gene was also more frequent among LC patients (49%; p = 0.045). Additionally, the frequencies of LC symptoms were higher among carriers of IFNG genotypes AA than among non-AA genotypes (Z = 5.08; p < 0.0001).
Two polymorphisms were associated with LC in both inflammatory and thrombophilia pathways, thus reinforcing their role in LC. The higher frequencies of acute phase symptoms among LC and higher frequency of underlying comorbidities might suggest that acute disease severity and the triggering of preexisting condition may play a role in LC development.
Source: da Silva R, de Sarges KML, Cantanhede MHD, da Costa FP, dos Santos EF, Rodrigues FBB, de Nazaré do Socorro de Almeida Viana M, de Meira Leite M, da Silva ALS, de Brito MTM, da Silva Torres MK, Queiroz MAF, Vallinoto IMVC, Henriques DF, dos Santos CP, Viana GMR, Quaresma JAS, Falcão LFM, Vallinoto ACR, dos Santos EJM. Thrombophilia and Immune-Related Genetic Markers in Long COVID. Viruses. 2023; 15(4):885. https://doi.org/10.3390/v15040885 https://www.mdpi.com/1999-4915/15/4/885 (Full text)

Mechanistic factors contributing to pain and fatigue in fibromyalgia and ME/CFS: autonomic and inflammatory insights from an experimental medicine study

Abstract:

Background: Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathoaetiological mechanisms are complex and debated(2), however there is a strong association with features of hereditary disorders of connective tissue (hypermobility) and autonomic and inflammatory abnormalities (1,2).

Objectives: To determine potential autonomic and inflammatory mechanisms of pain and fatigue in fibromyalgia and ME/CFS

Methods: After excluding participants with WCC higher than 10 (suggesting acute infection) baseline markers of inflammation (CRP and ESR) were available for 60 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 23 matched controls. Participants then underwent full research diagnostic evaluation including a hypermobility assessment(1) and autonomic challenge (60 degree head up tilt, ISRCTN78820481). Subjective pain and fatigue were assessed before and after challenge (VAS). Linear regression models were used to explore predictors, with adjustment for confounders as appropriate. Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1)pain and 2)fatigue induced by challenge and mediatiors 1)no of connective tissue features in hypermobility diagnostic criteria endorsed by participant; 2)baseline inflammatory markers.

Results: ESR and CRP were significantly higher in patients rather than controls, even after correcting for BMI, age and sex (B=5.15, t=2.05, p=0.044; B=1.77, t=2.15, p=0.044 respectively). Adjusted ESR and CRP correlated with both subjective fatigue (B=0.44, t=2.09, p=0.04; B=1.63, t=2.60, p=0.011) and pain severity (B=0.13, t=2.51, p=0.014; B=0.45, t=3.01, p=0.004) at baseline. Autonomic challenge amplified pain (B=14.20, t=2.87, p=0.005) and fatigue (B=31.48, t=5.95, p=<0.001) in patients to a significantly greater degree than controls, controlling for baseline levels. Baseline ESR and CRP also predicted challenge-induced increase in fatigue (B=0.78, t=370, p=<0.001; B=1.91, t=3.36, p=<0.001) and ESR challenge-induced increases in pain (B=0.46, t=2.35, p=0.021).

Mediation analysis demonstrated that number of connective tissue features expressed in hypermobility criteria mediated the degree to which subjective pain was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero, 0.1572 – 6.8171). ESR mediated the degree to which subjective fatigue was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero,0.7541 – 7.3888).

Conclusion: To our knowledge this is the first study to directly explore autonomic and inflammatory mechanisms of pain and fatigue in a combined population of Fibromyalgia and ME/CFS. This study this adds to the evidence-base of baseline inflammatory abnormalities in fibromyalgia and ME/CFS. It highlights their potential role in predicting symptom severity and their potential mechanistic role in autonomic induced pain and fatigue, suggesting future treatment strategies.

Source: Eccles J, Thompson C, Thompson B, et al. AB1209 MECHANISTIC FACTORS CONTRIBUTING TO PAIN AND FATIGUE IN FIBROMYALGIA AND ME/CFS: AUTONOMIC AND INFLAMMATORY INSIGHTS FROM AN EXPERIMENTAL MEDICINE STUDY. Annals of the Rheumatic Diseases 2022;81:1719 https://ard.bmj.com/content/annrheumdis/81/Suppl_1/1719.2.full.pdf (Full text available as PDF file)

Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features

Abstract:

Many of the survivors of the novel coronavirus disease (COVID-19) are suffering from persistent symptoms, causing significant morbidity and decreasing their quality of life, termed “post-COVID-19 syndrome” or “long COVID”. Understanding the mechanisms surrounding PCS is vital to developing the diagnosis, biomarkers, and possible treatments.

Here, we describe the prevalence and manifestations of PCS, and similarities with previous SARS epidemics. Furthermore, we look at the molecular mechanisms behind the neurological features of PCS, where we highlight important neural mechanisms that may potentially be involved and pharmacologically targeted, such as glutamate reuptake in astrocytes, the role of NMDA receptors and transporters (EAAT2), ROS signaling, astrogliosis triggered by NF-κB signaling, KNDy neurons, and hypothalamic networks involving Kiss1 (a ligand for the G-protein-coupled receptor 54 (GPR54)), among others. We highlight the possible role of reactive gliosis following SARS-CoV-2 CNS injury, as well as the potential role of the hypothalamus network in PCS manifestations.

Source: Mohamed MS, Johansson A, Jonsson J, Schiöth HB. Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features. Int J Mol Sci. 2022 Apr 12;23(8):4275. doi: 10.3390/ijms23084275. PMID: 35457093. https://www.mdpi.com/1422-0067/23/8/4275/htm (Full text)

A Causal-Pathway Phenotype of Chronic Fatigue Syndrome due to Hemodialysis in Patients with End-Stage Renal Disease

Abstract:

Background: End-stage renal disease (ESRD) is associated with fatigue and physio-somatic symptoms.

Objective: To delineate the associations between severity of fatigue and physio-somatic symptoms and glomerular filtration rate, inflammatory biomarkers, and Wnt/catenin-pathway proteins.

Methods: The Wnt-pathway related proteins β-catenin, Dickkopf-related protein 1 (DKK1), R-spondin-1, and sclerostin were measured by ELISA technique in 60 ESRD patients and 30 controls. The Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to assess the severity of FF symptoms.

Results: ESRD is characterized by a significant increase in the total FF score, muscle tension, fatigue, sadness, sleep disorders, gastro-intestinal (GI) symptoms, and a flu-like malaise. The total-FF score was significantly correlated with serum levels of urea, creatinine, and copper (positively), and β-catenin, eGFR, hemoglobin, albumin, and zinc (inversely). The total-FF score was associated with the number of total dialysis and weekly dialysis sessions, and these dialysis characteristics were more important in predicting FF scores than eGFR measurements. Partial Least Squares analysis showed that the FF score comprised two factors that are differently associated with biomarkers: a) 43.0% of the variance in fatigue, GI symptoms, muscle tension, sadness, and insomnia is explained by hemoglobin, albumin, zinc, β-catenin, and R-spondin-1; and b) 22.3% of the variance in irritability, concentration and memory impairments by increased copper and cations/chloride ratio, and male sex.

Conclusion: ESRD patients show high levels of fatigue and physio-somatic symptoms, which are associated with hemodialysis and mediated by dialysis-induced changes in inflammatory pathways, the Wnt/catenin pathway, and copper.

Source: Asad HN, Al-Hakeim HK, Moustafa SR, Maes M. A Causal-Pathway Phenotype of Chronic Fatigue Syndrome due to Hemodialysis in Patients with End-Stage Renal Disease. CNS Neurol Disord Drug Targets. 2022 Apr 1. doi: 10.2174/1871527321666220401140747. Epub ahead of print. PMID: 35366785. https://pubmed.ncbi.nlm.nih.gov/35366785/

Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Abstract:

Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) has been classified as a disease of the central nervous system by the WHO since 1969. Many patients carrying this diagnosis do demonstrate an almost bewildering array of biological abnormalities particularly the presence of oxidative and nitrosative stress (O&NS) and a chronically activated innate immune system.

The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS. Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels.

Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism (e.g. compromised ATP production) and dysfunctional intracellular signaling pathways. The interplay between all of these factors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory and autoimmune pathways which may sustain the disease.

 

Source: Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014 Mar;12(2):168-85. doi: 10.2174/1570159X11666131120224653. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964747/ (Full article)