Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue

Fevang, Børre; Wyller, Vegard Bruun; Mollnes, Tom Eirik; Pedersen, Maria; Asprusten, Tarjei Tørre; Michelsen, Annika E.; Ueland, Thor; Otterdal, Kari

doi:10.3389/fimmu.2021.715102

Cited by 15 publications

(23 citation statements)

References 25 publications

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“…It has been suggested that infections by viruses or bacteria can lead to immune dysregulation, manifesting in the observed fatigue symptoms ( 13 ). Epstein-Barr virus infection has been associated with ME/CFS symptoms since the 1980s ( 30 – 33 ). Recently, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has also been reported to cause persisting ME/CFS–like symptoms in a subset of recovered patients [termed as long coronavirus disease 2019 (long COVID), post–COVID-19 syndrome, or chronic COVID syndrome] ( 34 – 38 ), with implications for studying “classical” ME/CFS ( 39 ).…”

Section: Introductionmentioning

confidence: 99%

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Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients

et al. 2022

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with an unclear etiology and pathogenesis. Both an involvement of the immune system and gut microbiota dysbiosis have been implicated in its pathophysiology. However, potential interactions between adaptive immune responses and the microbiota in ME/CFS have been incompletely characterized. Here, we profiled antibody responses of patients with severe ME/CFS and healthy controls against microbiota and viral antigens represented as a phage-displayed 244,000 variant library. Patients with severe ME/CFS exhibited distinct serum antibody epitope repertoires against flagellins of Lachnospiraceae bacteria. Training machine learning algorithms on this antibody-binding data demonstrated that immune responses against gut microbiota represent a unique layer of information beyond standard blood tests, providing improved molecular diagnostics for ME/CFS. Together, our results point toward an involvement of the microbiota-immune axis in ME/CFS and lay the foundation for comparative studies with inflammatory bowel diseases and illnesses characterized by long-term fatigue symptoms, including post–COVID-19 syndrome.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients

et al. 2022

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“…Gravelsina et al found a higher viral load of HHV-6B in peripheral blood mononuclear cells (PBMC) corresponding to the severity of ME/CFS symptoms, with 84.2% of patients with severe ME/CFS having a load greater than 1,000 copies per million PBMC compared to 57.1% of patients with mild ME/CFS and 11.1% of health controls ( Gravelsina et al, 2022 ). Fevang et al found a higher average copy number of EBV in the peripheral blood of ME/CFS patients compared to healthy controls, however the difference was not statistically significant ( Fevang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, several recent studies have identified higher copy numbers of HHV-6 and EBV in ME/CFS patients compared to healthy controls (Fevang et al, 2021;Lee et al, 2021;Gravelsina et al, 2022). Lee et al observed an association between HHV-6B and HHV-7 viral load and severity of ME/CFS symptoms by analyzing salivary viral load.…”

Section: Discussionmentioning

confidence: 99%

Tissue specific signature of HHV-6 infection in ME/CFS

Kasimir

Toomey

Liu

et al. 2022

Front. Mol. Biosci.

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First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development. HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer’s Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome. Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls. Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.

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“…All IM symptoms and complications are associated with T-cell activation and cytokine production (19,20). T cells from children with AIM were highly activated by the high expression of the How PD-1 regulates T cell exhaustion during chronic viral infection has been extensively researched (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Characteristics of immunological events in Epstein-Barr virus infection in children with infectious mononucleosis

et al. 2023

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Backgrounds & aimsEpstein-Barr virus (EBV) infection occurs commonly in children and may cause acute infectious mononucleosis (AIM) and various malignant diseases. Host immune responses are key players in the resistance to EBV infection. We here assessed the immunological events and laboratory indicators of EBV infection, as well as determined the clinical usefulness of evaluating the severity and efficacy of antiviral therapy in AIM patients.MethodsWe enrolled 88 children with EBV infection. The immune environment was defined by immunological events such as frequencies of lymphocyte subsets, phenotypes of T cells, and their ability to secrete cytokines, and so on. This environment was analyzed in EBV-infected children with different viral loads and in children in different phases of infectious mononucleosis (IM) from disease onset to convalescence.ResultsChildren with AIM had higher frequencies of CD3+ T and CD8+ T cells, but lower frequencies of CD4+ T cells and CD19+ B cells. In these children, the expression of CD62L was lower and that of CTLA-4 and PD-1 was higher on T cells. EBV exposure induced granzyme B expression, but reduced IFN-γ secretion, by CD8+ T cells, whereas NK cells exhibited reduced granzyme B expression and increased IFN-γ secretion. The frequency of CD8+ T cells was positively correlated with the EBV DNA load, whereas the frequencies of CD4+ T cells and B cells were negatively correlated. During the convalescent phase of IM, CD8+ T cell frequency and CD62L expression on T cells were restored. Moreover, patient serum levels of IL-4, IL-6, IL-10, and IFN-γ were considerably lower throughout the convalescent phase than throughout the acute phase.ConclusionRobust expansion of CD8+ T cells, accompanied by CD62L downregulation, PD-1 and CTLA-4 upregulation on T cells, enhanced granzyme B production, and impaired IFN-γ secretion, is a typical characteristic of immunological events in children with AIM. Noncytolytic and cytolytic effector functions of CD8+ T cells are regulated in an oscillatory manner. Furthermore, the AST level, number of CD8+ T cells, and CD62L expression on T cells may act as markers related to IM severity and the effectiveness of antiviral treatment.

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Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue

Cited by 15 publications

References 25 publications

Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients

Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients

Tissue specific signature of HHV-6 infection in ME/CFS

Characteristics of immunological events in Epstein-Barr virus infection in children with infectious mononucleosis

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