Tag: interferon-gamma

Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment

Abstract:

As the heterogeneity of symptoms is increasingly recognized among long-COVID patients, it appears highly relevant to study potential pathophysiological differences along the different subtypes. Preliminary evidence suggests distinct alterations in brain structure and systemic inflammatory patterns in specific groups of long-COVID patients.

To this end, we analyzed differences in cortical thickness and peripheral immune signature between clinical subgroups based on 3T-MRI scans and signature inflammatory markers in n=120 participants comprising healthy never-infected controls, healthy COVID-19 survivors, and subgroups of long-COVID patients with and without cognitive impairment according to screening with Montreal Cognitive Assessment.

Whole-brain comparison of cortical thickness between the 4 groups was conducted by surface-based morphometry. We identified distinct cortical areas showing a progressive increase in cortical thickness across different groups, starting from healthy individuals who had never been infected with COVID-19, followed by healthy COVID-19 survivors, long-COVID patients without cognitive deficits (MoCA ≥ 26), and finally, long-COVID patients exhibiting significant cognitive deficits (MoCA < 26). These findings highlight the continuum of cortical thickness alterations associated with COVID-19, with more pronounced changes observed in individuals experiencing cognitive impairment (p<0.05, FWE-corrected).

Affected cortical regions covered prefrontal and temporal gyri, insula, posterior cingulate, parahippocampal gyrus, and parietal areas. Additionally, we discovered a distinct immunophenotype, with elevated levels of IL-10, IFNg, and sTREM2 in long-COVID patients, especially in the group suffering from cognitive impairment.

We demonstrate lingering cortical and immunological alterations in healthy and impaired subgroups of COVID-19 survivors. This implies a complex underlying pathomechanism in long-COVID and emphasizes the necessity to investigate the whole spectrum of post-COVID biology to determine targeted treatment strategies targeting specific sub-groups.

Source: Bianca Besteher, Tonia Rocktaeschel, Alejandra Patricia Garza, Marlene Machnik, Johanna Ballez, Dario Lucas Helbing, Katrhin Finke, Philipp Reuken, Daniel Guellmar, Christian Gaser, Martin Walter, Nils Opel, Ildiko Rita Dunay. Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment. medRxiv 2023.07.21.23292988; doi: https://doi.org/10.1101/2023.07.21.23292988 https://www.medrxiv.org/content/10.1101/2023.07.21.23292988v1v (Full text available as PDF file)

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19

Abstract:

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed.

We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls.

In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis.

Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

Source: Paniskaki K, Konik MJ, Anft M, Heidecke H, Meister TL, Pfaender S, Krawczyk A, Zettler M, Jäger J, Gaeckler A, Dolff S, Westhoff TH, Rohn H, Stervbo U, Scheibenbogen C, Witzke O, Babel N. Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19. Front Microbiol. 2023 Jun 2;14:1196721. doi: 10.3389/fmicb.2023.1196721. PMID: 37333646; PMCID: PMC10272838. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272838/ (Full text)

Positive Effects of Probiotic Therapy in Patients with Post-Infectious Fatigue

Abstract:

Post-infectious fatigue is a common complication that can lead to decreased physical efficiency, depression, and impaired quality of life. Dysbiosis of the gut microbiota has been proposed as a contributing factor, as the gut–brain axis plays an important role in regulating physical and mental health. This pilot study aimed to investigate the severity of fatigue and depression, as well as the quality of life of 70 patients with post-infectious fatigue who received a multi-strain probiotic preparation or placebo in a double-blind, placebo-controlled trial.
Patients completed questionnaires to assess their fatigue (fatigue severity scale (FSS)), mood (Beck Depression Inventory II (BDI-II)), and quality of life (short form-36 (SF-36)) at baseline and after 3 and 6 months of treatment. Routine laboratory parameters were also assessed, including immune-mediated changes in tryptophan and phenylalanine metabolism.
The intervention was effective in improving fatigue, mood, and quality of life in both the probiotic and placebo groups, with greater improvements seen in the probiotic group. FSS and BDI-II scores declined significantly under treatment with both probiotics and placebo, but patients who received probiotics had significantly lower FSS (p < 0.001) and BDI-II (p < 0.001) scores after 6 months.
Quality of life scores improved significantly in patients who received probiotics (p < 0.001), while patients taking a placebo only saw improvements in the “Physical limitation” and “Energy/Fatigue” subcategories. After 6 months neopterin was higher in patients receiving placebo, while no longitudinal changes in interferon-gamma mediated biochemical pathways were observed.
These findings suggest that probiotics may be a promising intervention for improving the health of patients with post-infectious fatigue, potentially through modulating the gut–brain axis.
Source: Obermoser K, Brigo N, Schroll A, Monfort-Lanzas P, Gostner JM, Engl S, Geisler S, Knoll M, Schennach H, Weiss G, Fuchs D, Bellmann-Weiler R, Kurz K. Positive Effects of Probiotic Therapy in Patients with Post-Infectious Fatigue. Metabolites. 2023; 13(5):639. https://doi.org/10.3390/metabo13050639 https://www.mdpi.com/2218-1989/13/5/639 (Full text)

Cytokine deficiencies in patients with Long-COVID

Abstract:

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood. We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of Interferon Gamma (IFNγ) and Interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

Source: Williams ES, Martins TB, Shah KS, Hill HR, Coiras M, Spivak AM, Planelles V. Cytokine Deficiencies in Patients with Long-COVID. J Clin Cell Immunol. 2022;13(6):672. Epub 2022 Nov 18. PMID: 36742994; PMCID: PMC9894377. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894377/ (Full text)

Long Covid and Neurodegenerative Disease

Abstract:

Brain fog with compromised ability to concentrate has been the most frequent Long Covid (LC) complaint. This is due to an increased TGF beta/IFN gamma with consequently increased bradykinin (BKN), especially in Caucasian females. Brain and lung blood vessels “leak.” This same ratio is increased in Alzheimer’s disease (AD), but decreased in Parkinson’s disease (PD), because CD4+ and CD8+ T cells are differentially affected by the invading associated viruses, e.g., SARS CoV2, HIV, ….

In Covid-19 CD147 receptors on immune cells are critical in generating the increased TGF beta/IFN gamma and those on endothelial cells, platelets, and erythrocytes are critical to the abnormal microvascular blood flow. ACE2 receptors on pneumocytes and enterocytes enable pulmonary and GI entry, initiating gut dysbiosis.

Epigenetics, methylation, magnesium, vitamin D, the B vitamins, and antioxidants suggest that these issues can be surmounted. Biochemical, physiologic, and epidemiologic data are analyzed to answer these questions. An LC model is presented and discussed in the context of the most recent research. Suggestions to avoid these and other worrisome concerns are included. Other topics discussed include estrogen, the gut microbiome, type 2 diabetes (T2D), and homocysteine.

Source: Chambers, P. Long Covid and Neurodegenerative Disease. Preprints 2023, 2023020027 (doi: 10.20944/preprints202302.0027.v1) https://www.preprints.org/manuscript/202302.0027/v1 (Full text available as PDF file)

 

T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID

Abstract:

Many people experiencing long COVID syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC), suffer from debilitating neurologic symptoms (Neuro-PASC). However, whether virus-specific adaptive immunity is affected in Neuro-PASC patients remains poorly understood. We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated humoral and cellular responses toward SARS-CoV-2 Nucleocapsid protein at an average of 6 months post-infection compared to healthy COVID convalescents. Neuro-PASC patients also had enhanced virus-specific production of IL-6 from and diminished activation of CD8+ T cells.

Furthermore, the severity of cognitive deficits or quality of life disturbances in Neuro-PASC patients were associated with a reduced diversity of effector molecule expression in T cells but elevated IFN-γ production to the C-terminal domain of Nucleocapsid protein. Proteomics analysis showed enhanced plasma immunoregulatory proteins and reduced pro-inflammatory and antiviral response proteins in Neuro-PASC patients compared with healthy COVID convalescents, which were also correlated with worse neurocognitive dysfunction. These data provide new insight into the pathogenesis of long COVID syndrome and a framework for the rational design of predictive biomarkers and therapeutic interventions.

One Sentence Summary Adaptive immunity is altered in patients with neurologic manifestations of long COVID.

Source: Lavanya Visvabharathy, Barbara A. Hanson, Zachary S. Orban, Patrick H. Lim, Nicole M. Palacio, Millenia Jimenez, Jeffrey R. Clark, Edith L. Graham, Eric M. Liotta, George Tachas, Pablo Penaloza-MacMaster, Igor J. Koralnik. T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID. medRxiv 2021.08.08.21261763; doi: https://doi.org/10.1101/2021.08.08.21261763 https://www.medrxiv.org/content/10.1101/2021.08.08.21261763v4.full-text (Full text)

Genetic and epigenetic regulation of Catechol-O-methyltransferase in relation to inflammation in chronic fatigue syndrome and Fibromyalgia

Abstract:

Background: Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM). We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM.

Methods: A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days. The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β).

Results: COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients.

Discussion: Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM. Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes.

Source: Polli A, Hendrix J, Ickmans K, Bakusic J, Ghosh M, Monteyne D, Velkeniers B, Bekaert B, Nijs J, Godderis L. Genetic and epigenetic regulation of Catechol-O-methyltransferase in relation to inflammation in chronic fatigue syndrome and Fibromyalgia. J Transl Med. 2022 Oct 25;20(1):487. doi: 10.1186/s12967-022-03662-7. PMID: 36284330; PMCID: PMC9598022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598022/ (Full text)

Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID

Abstract:

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood.

We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of interferon gamma (IFNγ) and interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

Source: Williams ESCP, Martins TB, Hill HR, Coiras M, Shah KS, Planelles V, Spivak AM. Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID. medRxiv [Preprint]. 2022 Oct 5:2022.10.03.22280661. doi: 10.1101/2022.10.03.22280661. PMID: 36238724; PMCID: PMC9558442. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558442/ (Full text)

Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients

Abstract:

Advancements in nucleic acid sequencing technology combined with an unprecedented availability of metadata have revealed that 45% of the human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically necessary. Dysregulation of TEs, including human retroviral endogenous sequences (HERVs) has been shown to associate with several neurologic and autoimmune diseases, including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, no study has yet addressed whether abnormal expression of these sequences correlates with fibromyalgia (FM), a disease frequently comorbid with ME/CFS.

The work presented here shows, for the first time, that, in fact, HERVs of the H, K and W types are overexpressed in immune cells of FM patients with or without comorbid ME/CFS. Patients with increased HERV expression (N = 14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. The findings reported in this study could explain the flu-like symptoms FM patients present with in clinical practice, in the absence of concomitant infections. Future work aimed at identifying specific genomic loci differentially affected in FM and/or ME/CFS is warranted.

Source: Ovejero T, Sadones O, Sánchez-Fito T, Almenar-Pérez E, Espejo JA, Martín-Martínez E, Nathanson L, Oltra E. Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients. Int J Mol Sci. 2020 Feb 18;21(4). pii: E1366. doi: 10.3390/ijms21041366. https://www.mdpi.com/1422-0067/21/4/1366 (Full text)

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions.

We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation.

Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity).

In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

Source: Ece Karhan, Courtney L Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, Peter N Robinson, Suzanne D Vernon, Lucinda Bateman, Derya Unutmaz. Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
bioRxiv 2019.12.23.887505; doi: https://doi.org/10.1101/2019.12.23.887505 https://www.biorxiv.org/content/10.1101/2019.12.23.887505v1 (Full text available as PDF file)