Abstract

We have identified a new class of pathogen-associated molecular pattern (PAMP) proteins (deoxyuridine triphosphate nucleotidohydrolases; dUTPases) that have novel immunoregulatory and neuroregulatory functions that may contribute to the pathophysiology of diseases caused by human herpesviruses. Using the Epstein-Barr virus (EBV)- dUTPase as the prototype, our pioneering studies have demonstrated conclusively that the EBV-dUTPase induces sickness and anxiety behavior and impaired learning/memory effects independent of its enzymatic activity. Furthermore, the properties of the EBV- dUTPase were enhanced by stress. This multidisciplinary research grant will provide new information on the mechanism by which stress can impact the EBV-dUTPase-mediated effects as it relates to chronic fatigue syndrome.

Public Health Relevance

We have identified a new class of pathogen-associated molecular pattern (PAMP) proteins (deoxyuridine triphosphate nucleotidohydrolases; dUTPases) that have novel immunoregulatory and neuroregulatory functions that may contribute to the pathophysiology of diseases caused by human herpesviruses. Using the Epstein-Barr virus (EBV)- dUTPase as the prototype, our pioneering studies have demonstrated conclusively that the EBV-dUTPase induces sickness and anxiety behavior and impaired learning/memory effects independent of its enzymatic activity. Furthermore, the properties of the EBV- dUTPase were enhanced by stress. This multidisciplinary research grant will provide new information on the mechanism by which stress can impact the EBV-dUTPase-mediated effects as it relates to chronic fatigue syndrome.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084898-10
Application #
9665672
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Beisel, Christopher E
Project Start
2009-12-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2021-03-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Ohio State University
Department
Genetics
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210

  Publications

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