Epstein–Barr virus‐encoded dUTPase modulates immune function and induces sickness behavior in mice

Abstract

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis (IM). In addition, latent infections with EBV are associated with nasopharyngeal carcinoma (NPC) and Burkitt's Lymphoma (BL). Antibodies to several EBV-encoded early antigens (EA) are often observed in patients with NPC and BL, however, the role of EBV-encoded proteins in the etiology of these and other EBV-associated diseases is not completely understood. The EA complex encodes for at least six different viral enzymes including deoxyuridine triphosphate nucleotidohydrolase (dUTPase). dUTPase has recently been shown to modulate activation of human peripheral blood mononuclear cells in vitro (unpublished data). Therefore, these studies were designed to test whether dUTPase would modulate immune function in an in vivo model. Mice were injected with purified EBV dUTPase, and baseline immune function and sickness behaviors were measured. EBV dUTPase treatment inhibited replication of mitogen-stimulated lymphocytes obtained from treated mice. These lymphocytes were also less able to synthesize interferon-gamma after re-stimulation. In addition, treatment with dUTPase induced sickness behaviors. For example, as compared to control animals, dUTPase-treated animals lost body mass, had elevated body temperature, and displayed diminished locomotor activity. These data suggest that individual viral proteins may play a role in the pathophysiology of EBV associated disease.

Stress-Induced Immune Dysregulation: Implications for Wound Healing, Infectious Disease and Cancer

“…In a series of studies, we showed that purified EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) induced immune dysregulation in mice. Mice treated with the EBV encoded dUTPase also exhibited sickness behavior (Padgett et al 2004). Moreover, the EBV-encoded dUTPase treatment induced immune dysregulation in vitro by interfering with the replication of human PBMCs and inducing monocytes/macrophages to produce proinflammatory cytokines (Glaser et al 2006).…”

Epstein–Barr virus (EBV)-encoded dUTPase and chronic restraint induce impaired learning and memory and sickness responses

“…The EBV genome encodes proteins that form an early antigen complex important for viral replication [14]. Administration of individual EBV-encoded proteins, such as EBV-encoded dUTPase, allows the effects of EBV to be studied independent of infectious viral replication.…”

“…A 10 μg dose of EBV dUTPase for 14 days has been previously used to induce sickness behavior in mice [14]. ZT is a standard of time based on the period of a zeitgeber, ZT 0 is defined as the time when the lights come on and in this study ZT 14 is when the lights went off.…”

“…The ability of EBV-encoded dUTPase to dysregulate immune function suggests that it may play a role in the pathophysiology of EBV infection [10–13]. In a previous study we reported that EBV-encoded dUTPase induces sickness responses in mice, characterized by increased temperature and reduced activity [14]. Splenic and lymphatic cells taken from EBV-encoded dUTPase-injected mice reduced proliferation of T-cells and production of inflammatory cytokine interferon-γ when stimulated with a T-cell mitogen [14].…”

Immune Evasion by Epstein-Barr Virus

“…In a mouse model, dUTPase compromises lymphocyte responses, e.g., secretion of IFNγ (Padgett et al 2004). In human cells, EBV dUTPase has seemingly opposing effects: It induces NF-κB activation in a TLR2/MyD88-dependent way (Ariza et al 2009(Ariza et al , 2013Waldman et al 2008); it inhibits lymphocyte proliferation; and it induces production of both proinflammatory cytokines as well as IL-10 ( Brooks et al 2006;Glaser et al 2006).…”