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