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Role for EBV- & HHV-6A-dUTPases on Immune Dysfunction in ME/CFS and other Chronic Multi-Symptom Illnesses

Cox, Brandon Shelby
http://orcid.org/0000-0001-6753-6211
http://rave.ohiolink.edu/etdc/view?acc_num=osu1717254322674078

Abstract Details

2024, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic multi-symptom illness (CMI) characterized by fatigue, immune dysfunction, cognitive deficits, and metabolic defects persisting for over 6 months. There is currently no known cause, cure, or biomarkers for diagnosis of ME/CFS. ME/CFS diagnosis is currently based on adherence to specific case criteria, however the use of multiple different case criteria has led to inconsistencies in patient diagnosis and the data reported in ME/CFS research. This has further created a desperate need to identify biomarkers for diagnosis and/or stratification of ME/CFS patients to provide better patient care and to move the ME/CFS research field forward. Chapter 1 introduces the human herpesviruses Epstein-Barr Virus (EBV) and human herpesvirus 6A (HHV-6A) that have long been implicated as potential etiological agents for this disease and reviews the literature related to EBV- and HHV-6A-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) proteins, ME/CFS, and potential biological mechanisms connecting the two. Between 95-97% of the human population is infected with EBV and HHV-6A, which typically exist in a latent state within the host. These herpesviruses can be reactivated due to triggers such as stress or immune activation in which case they may undergo lytic or abortive-lytic replication. While lytic replication results in new viral progeny being formed, abortive-lytic replication only results in the production of immediate-early and early viral proteins. Herpesvirus-encoded dUTPase proteins are early gene products of herpesvirus reactivation and are reported to have immunomodulatory properties independent of their enzymatic activity such as activating NF-κB, stimulating the production of pro-inflammatory cytokines and modulating the expression of genes involved in innate and adaptive immunity. Reports that ME/CFS patients have elevated serum levels of antibodies against multiple herpesvirus dUTPases suggest heightened herpesvirus reactivation in these patients, however few studies have attempted to discern a mechanistic role for these dUTPases in ME/CFS. The studies presented in this dissertation will begin to elucidate what that role is, determining potential mechanisms by which the EBV- and HHV-6-dUTPase can affect ME/CFS pathophysiology. In chapter 2 I examined a large ME/CFS cohort and controls and demonstrated a significant increase in activin A and IL-21 serum levels, which correlated with seropositivity for antibodies against the EBV- and HHV-6-dUTPases but no increase in CXCL13. These cytokines are critical for T follicular helper (TFH) cell differentiation and for the generation of high-affinity antibodies and long-lived plasma cells. Notably, ME/CFS serum was sufficient to drive TFH cell differentiation via an activin A–dependent mechanism. The lack of simultaneous CXCL13 increase with IL-21 indicates impaired TFH function in ME/CFS. In vitro studies revealed that virus dUTPases strongly induced activin A secretion while in vivo, EBV-dUTPase induced the formation of splenic marginal zone B and invariant natural killer TFH (NKTFH) cells. Together, my data indicate abnormal germinal center (GC) activity in participants with ME/CFS and highlight a mechanism by which EBV- and HHV-6-dUTPases may alter GC and extrafollicular antibody responses. In chapter 3, examination of three cohorts of “healthy asymptomatic” individuals (n = 255) for the presence of antibodies against the herpesviruses dUTPase as a marker for lytic/abortive-lytic replication demonstrated that all cohorts exhibited differential anti-herpesvirus dUTPase antibodies positivity frequencies ranging from 40.4% to 84% with some individuals in these cohorts expressing antibodies to the dUTPases of multiple herpesviruses (17.2%–56%). Furthermore, our results demonstrate that there was a statistically significant difference in anti-human herpesvirus 6- (HHV-6) dUTPase antibodies in Cohort 3 (age = 66.2 ± 15.02 years) versus Cohort 1 (age 46.88 ± 8.61 years), suggesting that reactivation of HHV-6 A/B is not attenuated by aging. It is well established/documented that herpesvirus dUTPases induce immune dysfunction, as such it is of critical importance that additional studies be performed to determine how these viral proteins alter immune responses in asymptomatic individuals. In chapter 4, I sought to determine the potential role of herpesvirus reactivation and antiviral response status in the development of chronic multi-symptom illness (CMI) and Gulf War illness (GWI). Longitudinal sera samples from a CMI cohort (n = 40) and GWI cohort (n= 12) as well as a healthy control cohort (n = 20) were analyzed for herpesvirus dUTPase IgG antibodies and inflammatory cytokines/chemokines by viral dUTPase-specific ELISAs, single or multi-analyte cytokine/chemokine ELISAs, respectively as well as vitamin D status using ADVIA Centaur XPT immunoassay. The CMI and GWI cohorts exhibited a significant increase in the levels of anti-dUTPase antibodies to multiple herpesviruses when compared to the healthy control cohort (67% vs 5%). The CMI cohort exhibited elevated levels of monocyte chemoattractant protein 1 (MCP-1) when comparted to the GWI and control cohorts. Interestingly, an inverse relationship between serum interferon-gamma (IFN-γ) levels and anti-herpesvirus dUTPase antibodies was observed in the CMI cohort but not in the GWI or control cohorts, suggesting aberrant anti-viral response and immune dysfunction in the CMI cohort. My data provides evidence supporting the premise that the decreased serum levels of IFN-γ along with heightened viral dUTPase IgG antibodies may be a useful biomarker to identify a subset of veterans diagnosed with CMI with a deficient anti-viral response. Altogether, the data presented here demonstrates novel immunomodulatory properties of the EBV- and HHV-6-dUTPases and how they can potentially affect immune system function in a subset of people with ME/CFS and other chronic multi-symptom illnesses. Additionally, these findings could be used to identify subsets of patients, allowing for more focused research towards understanding mechanisms that can affect disease pathophysiology and subsequently more targeted biomarkers and treatments for different subsets of patients. Future studies should attempt to validate these findings in other ME/CFS patient cohorts with different severities, and further elucidate the functionality of TFH cells in ME/CFS patients.
Maria Ariza (Advisor)
Marshall Williams (Committee Member)
Steve Oghumu (Committee Member)
Amanda Panfil (Committee Member)
Benjamin Kaffenberger (Committee Member)
192 p.
Biomedical Research

Recommended Citations

Citations

  • Cox, B. S. (2024). Role for EBV- & HHV-6A-dUTPases on Immune Dysfunction in ME/CFS and other Chronic Multi-Symptom Illnesses [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1717254322674078

    APA Style (7th edition)

  • Cox, Brandon. Role for EBV- & HHV-6A-dUTPases on Immune Dysfunction in ME/CFS and other Chronic Multi-Symptom Illnesses. 2024. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1717254322674078.

    MLA Style (8th edition)

  • Cox, Brandon. "Role for EBV- & HHV-6A-dUTPases on Immune Dysfunction in ME/CFS and other Chronic Multi-Symptom Illnesses." Doctoral dissertation, Ohio State University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=osu1717254322674078

    Chicago Manual of Style (17th edition)

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© 2024, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.