Work from our laboratory has focused on the pathophysiology of Epstein-Barr virus (EBV), a gamma herpesvirus which is associated with several human malignancies including B-cell lymphoma and nasopharyngeal carcinoma. We have also explored the role that psychological stress plays in the modulation of the steady state expression of EBV early proteins and how stress could be a factor in the risk for EBV associated disease. This proposal will focus on how EBV can induce inflammation in vitro and in mice. We have explored the hypothesis that EBV-encoded early proteins can induce immune changes observed in patients infected with EBV independent of their role in viral replication. We discovered that EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) up-regulates the production of several proinflammatory cytokines including TNF-a, IL-1?, IL-6, IL-8, as well as IL-10 in macrophages. When purified EBV-encoded dUTPase was inoculated into mice the protein was capable of producing symptoms compatible with cytokine-induced sickness behavior. The data demonstrate that EBV-encoded dUTPase can induce sickness behavior in mice resulting in increased body temperature and decreased body mass and physical activity. Furthermore, there is new and extensive literature linking chronic inflammation with an increased risk for cancer. Our data provide a new perspective on how a latent herpes virus, such as EBV, when reactivated by stress or other factors, could cause immune dysregulation, the activation in NF?B in macrophages and the upregulation of proinflammatory cytokines with possible implications for EBV associated clinical symptoms and disease, including EBV associated tumors.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Beisel, Christopher E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Schools of Medicine
United States
Zip Code
Halpin, Peter; Williams, Marshall Vance; Klimas, Nancy G et al. (2017) Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses-encoded dUTPase: Implications in disease pathophysiology. J Med Virol 89:1636-1645
Saito, Toshie; Miyagawa, Kazuya; Chen, Shih-Yu et al. (2017) Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension. Circulation 136:1920-1935
Williams, Marshall V; Cox, Brandon; Ariza, Maria Eugenia (2016) Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease. Pathogens 6:
Aubrecht, Taryn G; Weil, Zachary M; Abi Salloum, Bachir et al. (2015) Chronic Physical Stress Does Not Interact with Epstein-Barr Virus (EBV)-Encoded Dutpase to Alter the Sickness Response. J Behav Brain Sci 5:513-523
Aubrecht, Taryn G; Weil, Zachary M; Ariza, Maria Eugenia et al. (2014) Epstein-Barr virus (EBV)-encoded dUTPase and chronic restraint induce impaired learning and memory and sickness responses. Physiol Behav 137:18-24
Stowe, Raymond P; Ruiz, R Jeanne; Fagundes, Christopher P et al. (2014) An ELISA method to compute endpoint titers to Epstein-Barr virus and cytomegalovirus: application to population-based studies. J Immunol Methods 408:64-9
Binkley, Philip F; Cooke, Glen E; Lesinski, Amanda et al. (2013) Evidence for the role of Epstein Barr Virus infections in the pathogenesis of acute coronary events. PLoS One 8:e54008
Ariza, Maria Eugenia; Rivailler, Pierre; Glaser, Ronald et al. (2013) Epstein-Barr virus encoded dUTPase containing exosomes modulate innate and adaptive immune responses in human dendritic cells and peripheral blood mononuclear cells. PLoS One 8:e69827
Lerner, A Martin; Ariza, Maria E; Williams, Marshall et al. (2012) Antibody to Epstein-Barr virus deoxyuridine triphosphate nucleotidohydrolase and deoxyribonucleotide polymerase in a chronic fatigue syndrome subset. PLoS One 7:e47891
Christian, Lisa M; Iams, Jay D; Porter, Kyle et al. (2012) Epstein-Barr virus reactivation during pregnancy and postpartum: effects of race and racial discrimination. Brain Behav Immun 26:1280-7