Tag: systemic inflammation

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract:

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog.

Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog.

Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers.

Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Source: Greene C, Connolly R, Brennan D, Laffan A, O’Keeffe E, Zaporojan L, O’Callaghan J, Thomson B, Connolly E, Argue R, Martin-Loeches I, Long A, Cheallaigh CN, Conlon N, Doherty CP, Campbell M. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci. 2024 Mar;27(3):421-432. doi: 10.1038/s41593-024-01576-9. Epub 2024 Feb 22. PMID: 38388736; PMCID: PMC10917679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917679/ (Full text)

Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α

Abstract:

The cGAS-STING pathway appears to contribute to dysregulated inflammation during coronavirus disease 2019 (COVID-19); however, inflammatory factors related to long COVID are still being investigated.

In the present study, we evaluated the association of cGAS and STING gene expression levels and plasma IFN-α, TNF-α and IL-6 levels with COVID-19 severity in acute infection and long COVID, based on analysis of blood samples from 148 individuals, 87 with acute COVID-19 and 61 in the post-COVID-19 period.

Quantification of gene expression was performed by real-time PCR, and cytokine levels were quantified by ELISA and flow cytometry. In acute COVID-19, cGAS, STING, IFN-α, TNF-α, and IL-6 levels were higher in patients with severe disease than in those with nonsevere manifestations (p < 0.05). Long COVID was associated with elevated cGAS, STING and IFN-α levels (p < 0.05).

Activation of the cGAS-STING pathway may contribute to an intense systemic inflammatory state in severe COVID-19 and, after infection resolution, induce an autoinflammatory disease in some tissues, resulting in long COVID.

Source: Queiroz, M.A.F., Brito, W.R.S., Pereira, K.A.S. et al. Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α. Sci Rep 14, 4974 (2024). https://doi.org/10.1038/s41598-024-55696-0 https://www.nature.com/articles/s41598-024-55696-0 (Full text)

Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview

Abstract:

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown causes characterised by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS); fibromyalgia (FM); and more recently post-COVID-19 condition (long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders.
Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. The accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and long COVID. To address this issue, this article aims to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, it aims to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.
Source: Mantle D, Hargreaves IP, Domingo JC, Castro-Marrero J. Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview. International Journal of Molecular Sciences. 2024; 25(1):574. https://doi.org/10.3390/ijms25010574 https://www.mdpi.com/1422-0067/25/1/574 (Full text)

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease after COVID-19 hospitalisation

Abstract:

One in ten SARS-CoV-2 infections result in prolonged symptoms termed long COVID, yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 previously hospitalised adults with long COVID grouped by symptoms. Elevated markers of myeloid inflammation and complement activation were associated with long COVID; elevated IL1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while MATN2 and DPP10 were elevated in gastrointestinal (GI) symptoms, and C1QA in cognitive impairment.
Proteins suggestive of neurodegeneration were elevated in cognitive impairment, whilst SCG3 (indicative of brain-gut axis disturbance) was specific to GI symptoms. Nasal inflammation was apparent after COVID-19 but did not associate with symptoms. Although SARS-CoV-2 specific IgG was elevated with some long COVID symptoms, virus was not detected from sputum. Thus, systemic inflammation is evident in long COVID and could be targeted in therapeutic trials tailored to pathophysiological differences between symptom groups.

Source: Peter Openshaw, Felicity Liew, Claudia Efstathiou et al. Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease after COVID-19 hospitalisation, 04 December 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3427282/v1] https://www.researchsquare.com/article/rs-3427282/v1 (Full text)

Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit

Abstract:

Approximately four months after recovering from a mild COVID-19 infection, around 25% of individuals developed visuoconstructive deficit (VCD), which was found to be correlated with an increase in peripheral immune markers and alterations in structural and metabolic brain imaging. Recently, it has been demonstrated that supplemental vitamin B12 regulates hyperinflammation during moderate and severe COVID-19 through methyl-dependent epigenetic mechanisms.

Herein, whole peripheral blood cultures were produced using samples obtained from patients with confirmed persistent VCD, and controls without impairment, between 10 and 16 months after mild COVID-19. This experimental model was used to assess the leukocyte expression patterns of 11 biomarkers previously associated with VCD in long COVID and explore the potential of pharmacological B12 in regulating these genes. The results showed that patients with persistent VCD displayed continued upregulation of CCL11 and LIF compared to controls.

It is worth noting that elevated serum levels of CCL11 have been previously linked to age-related neurodegenerative diseases. Notably, the addition of 1 nM of vitamin B12 to blood cultures from individuals with VCD normalized the mRNA levels of CCL11, upregulated the neuroprotective HGF, and, to a lesser extent, downregulated CSF2 and CXCL10. There was an inverse correlation observed between CCL11 mRNA levels and methylation levels of specific cytosines in its promoter region.

These findings underscore the significance of systemic inflammation in persistent VCD associated with long COVID. Moreover, the study provides evidence suggesting that B12, acting as an epidrug, shows promise as a therapeutic approach for addressing this cognitive impairment.

Source: Larissa Cassiano, Jonas Paula, Daniela Rosa et al. Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit, 11 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3158180/v1] https://www.researchsquare.com/article/rs-3158180/v1 (Full text)

Long-Term cognitive dysfunction after the COVID-19 pandemic: a narrative review

Abstract:

Introduction: SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has brought a conglomerate of novel chronic disabling conditions described as ‘Long COVID/Post-COVID-19 Syndrome’. Recent evidence suggests that the multifaceted nature of this syndrome results in both pulmonary and extrapulmonary sequelae, chronic dyspnoea, persistent fatigue, and cognitive dysfunction being the most common, debilitating symptoms. Several mechanisms engender or exacerbate cognitive impairment, including central nervous system (CNS) and extra-CNS causes, although the exact mechanism remains unclear. Both hospitalized and non-hospitalized patients may suffer varying degrees of cognitive impairment, ranging from fatigue and brain fog to prolonged deficits in memory and attention, detrimental to the quality-of-life years post-recovery. The aim of this review is to understand the underlying mechanisms, associations, and attempts for prevention with early intervention of long-term cognitive impairment post-COVID-19.

Methodology: A systematic search was conducted through multiple databases such as Medline, National Library of Medicine, Ovid, Scopus database to retrieve all the articles on the long term sequalae of cognitive dysfunction after Sars-Cov2 infection. The inclusion criteria included all articles pertinent to this specific topic and exclusion criteria subtracted studies pertaining to other aetiologies of cognitive dysfunction. This search was carefully screened for duplicates and the relevant information was extracted and analysed.

Results/discussion: To date, the exact pathogenesis, and underlying mechanisms behind cognitive dysfunction in COVID-19, remain unclear, hindering the development of adequate management strategies. However, the proposed mechanisms suggested by various studies include direct damage to the blood-brain barrier, systemic inflammation, prolonged hypoxia, and extended intensive care admissions. However, no clear-cut guidelines for management are apparent.

Conclusion: This review of the COVID-19 pandemic has elucidated a new global challenge which is affecting individuals’ quality of life by inducing long-term impaired cognitive function. We have found that comprehensive evaluations and interventions are crucial to address the cognitive sequelae in all COVID-19 patients, especially in patients with pre-existing cognitive impairment. Nevertheless, the authors recommend further research for the development of relevant, timely neurocognitive assessments and treatment plans.

Source: Shariff, Sanobar; Uwishema, Olivier; Mizero, Jocelyn; Devi Thambi, Vimala; Nazir, Abubakar; Mahmoud, Ashraf; Kaushik, Ikshwaki; Khayat, Saadeddine; Yusif Maigoro, Abdulkadir; Awde, Sara; Al Maaz, Zeina; Alwan, Iktimal; Hijazi, Mahdi; Wellington, Jack MSc (LSHTM) FGMS; Soojin, Lee. Long-Term cognitive dysfunction after the COVID-19 pandemic: a narrative review. Annals of Medicine & Surgery ():10.1097/MS9.0000000000001265, September 8, 2023. | DOI: 10.1097/MS9.0000000000001265 https://journals.lww.com/annals-of-medicine-and-surgery/abstract/9900/long_term_cognitive_dysfunction_after_the_covid_19.1011.aspx

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and optimizing disease tolerance

Abstract:

Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection.

The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation.

Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting nerve endings in the nasal cavity, likely from the trigeminal nerve, possibly activating additional centers in the brainstem of ME-patients and correlating with a ∼30% reduction in overall symptom scores after eight weeks of treatment.

By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover signs of chronic immune activation in ME, as well as immunological correlates of improvement that center around gut-homing immune cells and reduced inflammation.

The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We believe that these results are suggestive of ME as a condition explained by a maladaptive disease tolerance response following infection.

Source: Lucie Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin, Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and optimizing disease tolerance, Oxford Open Immunology, 2023;, iqad003, https://doi.org/10.1093/oxfimm/iqad003 (Full text available as PDF file)

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

Abstract:

Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple “omics” assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis.

Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses.

Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.

Source: Kailin Yin, Michael J. Peluso, Reuben Thomas, Min Gyoung Shin, Jason Neidleman, Xiaoyu Luo, Rebecca Hoh, Khamal Anglin, Beatrice Huang, Urania Argueta, Monica Lopez, Daisy Valdivieso, Kofi Asare, Rania Ibrahim, Ludger Ständker, Scott Lu, Sarah A. Goldberg, Sulggi A. Lee, Kara L. Lynch, J. Daniel Kelly, Jeffrey N. Martin, Jan Münch, Steven G. Deeks, Timothy J. Henrich, Nadia R. Roan. Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2. bioRxiv 2023.02.09.527892; doi: https://doi.org/10.1101/2023.02.09.527892 https://www.biorxiv.org/content/10.1101/2023.02.09.527892v1.full (Full text)

Vascular Function, Systemic Inflammation, and Coagulation Activation 18 Months after COVID-19 Infection: An Observational Cohort Study

Abstract:

Introduction: Among its effect on virtually all other organs, COVID-19 affects the cardiovascular system, potentially jeopardizing the cardiovascular health of millions. Previous research has shown no indication of macrovascular dysfunction as reflected by carotid artery reactivity, but has shown sustained microvascular dysfunction, systemic inflammation, and coagulation activation at 3 months after acute COVID-19. The long-term effects of COVID-19 on vascular function remain unknown.
Materials and Methods: This cohort study involved 167 patients who participated in the COVAS trial. At 3 months and 18 months after acute COVID-19, macrovascular dysfunction was evaluated by measuring the carotid artery diameter in response to cold pressor testing. Additionally, plasma endothelin-1, von Willebrand factor, Interleukin(IL)-1ra, IL-6, IL-18, and coagulation factor complexes were measured using ELISA techniques.
Results: The prevalence of macrovascular dysfunction did not differ between 3 months (14.5%) and 18 months (11.7%) after COVID-19 infection (p = 0.585). However, there was a significant decrease in absolute carotid artery diameter change, 3.5% ± 4.7 vs. 2.7% ± 2.5, p—0.001, respectively. Additionally, levels of vWF:Ag were persistently high in 80% of COVID-19 survivors, reflecting endothelial cell damage and possibly attenuated endothelial function. Furthermore, while levels of the inflammatory cytokines interleukin(IL)-1RA and IL-18 were normalized and evidence of contact pathway activation was no longer present, the concentrations of IL-6 and thrombin:antithrombin complexes were further increased at 18 months versus 3 months (2.5 pg/mL ± 2.6 vs. 4.0 pg/mL ± 4.6, p = 0.006 and 4.9 μg/L ± 4.4 vs. 18.2 μg/L ± 11.4, p < 0.001, respectively).
Discussion: This study shows that 18 months after COVID-19 infection, the incidence of macrovascular dysfunction as defined by a constrictive response during carotid artery reactivity testing is not increased. Nonetheless, plasma biomarkers indicate sustained endothelial cell activation (vWF), systemic inflammation (IL-6), and extrinsic/common pathway coagulation activation (FVII:AT, TAT) 18 months after COVID-19 infection.
Source: Willems LH, Jacobs LMC, Groh LA, ten Cate H, Spronk HMH, Wilson-Storey B, Hannink G, van Kuijk SMJ, Ghossein-Doha C, Nagy M, Thijssen DHJ, van Petersen AS, Warlé MC. Vascular Function, Systemic Inflammation, and Coagulation Activation 18 Months after COVID-19 Infection: An Observational Cohort Study. Journal of Clinical Medicine. 2023; 12(4):1413. https://doi.org/10.3390/jcm12041413 https://www.mdpi.com/2077-0383/12/4/1413 (Full text)

Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?

Abstract:

As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms.

Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.

Source: Sun Y, Koyama Y, Shimada S. Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation? Front Aging Neurosci. 2022 Jun 16;14:903455. doi: 10.3389/fnagi.2022.903455. PMID: 35783147; PMCID: PMC9244793. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244793/ (Full text)