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.

Public Health Relevance

This multidisciplinary research grant will provide new information on how stress can have an impact on the pathophysiology on herpesvirus associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084898-03
Application #
8239555
Study Section
Special Emphasis Panel (ZRG1-BBBP-N (05))
Program Officer
Beisel, Christopher E
Project Start
2010-04-15
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$653,356
Indirect Cost
$219,260
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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