10th International Virology Summit
The Ohio State University, USA
Title: Role of Herpesviruses dUTPases in the immune dysregulation associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Gulf war illness
Biography: Maria Eugenia Ariza
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Gulf war illness (GWI) are debilitating diseases presenting with complex immune, endocrine and neurological symptoms. Annual health care costs are estimated at $24 billion. Diagnosis is based on exclusion and there are currently no validated tests for definitive diagnosis of either syndrome. While there is accumulating evidence supporting the premise that some herpesviruses may act as possible triggers in ME/CFS, the mechanism by which they contribute to the pathogenesis of ME/CFS remains unclear. Our studies are the first to demonstrate that the deoxyuridine triphosphate nucleotidohydrolase (dUTPase) encoded by the human herpesviruses represents a new class of pathogen-associated molecular pattern (PAMP) proteins, which alter immune and neurocognitive functions. In this study, we demonstrate that ME/CFS and GWI patients’ sera exhibit reactivation of multiple herpesviruses, differential antibody expression patterns to the herpesviruses-encoded dUTPase early protein as well as increased autoantibodies to the human nuclear dUTPase. A significant increase in IL-21 levels was also observed in a cohort of ME/CFS patients. Interestingly, IL-21 is produced at high levels by CD4+ follicular helper T cell (TFH) and regulates germinal center (GC) B cell survival and plasma-cell differentiation. Further in vitro studies in primary human cells demonstrated that the EBV-dUTPase induced activin A secretion by dendritic cells, which lead to the increased formation of CD4+ follicular helper T cells (TFH) and subsequent production of IL-21 and CXCL13 by TFH. Our data suggest a role for the herpesviruses dUTPase proteins in the immune dysregulation and pathophysiology observed in these patients possibly by altering the GC reaction and antibody responses as well as inducing the production of pleiotropic cytokines. Thus, screening for the presence of anti-herpesvirus dUTPase antibodies in these patients may serve as useful diagnostic biomarkers for the selection of appropriate treatments.