title: Epstein-Barr virus (EBV)-encoded dUTPase and chronic restraint induce impaired learning and memory and sickness responses.
abstract: Most adult humans have been infected with Epstein-Barr virus (EBV) and carry the latent virus. The EBV genome codes for several proteins that form an early antigen complex important for viral replication; one of these proteins is deoxyuridine triphosphate nucleotidohydrolase (dUTPase). The EBV-encoded dUTPase can induce sickness responses in mice. Because stress can increase latent virus reactivation, we hypothesized that chronic restraint would exacerbate sickness behaviors elicited by EBV-encoded dUTPase. Male Swiss-Webster mice were injected daily for 15 days with either saline or EBV-encoded dUTPase. Additionally, half of the mice from each condition were either restrained for 3h daily or left undisturbed. Restraint stress impaired learning and memory in the passive avoidance chamber; impaired learning and memory was due to EBV-encoded dUTPase injected into restrained mice. EBV-encoded dUTPase induced sickness responses and restraint stress interacts with EBV-encoded dUTPase to exacerbate the sickness response. These data support a role for EBV-encoded dUTPase and restraint stress in altering the pathophysiology of EBV independent of viral replication.
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Taryn G
authors.initials: TG
authors.lastname: Aubrecht
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Weil
authors.affiliation: Department of Molecular Virology, Immunology & Medical Genetics, Columbus, OH 43210, USA.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Ariza
authors.affiliation: Department of Molecular Virology, Immunology & Medical Genetics, Columbus, OH 43210, USA.
authors.forename: Marshall
authors.initials: M
authors.lastname: Williams
authors.affiliation: Institute of Behavioral Medicine Research, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Reader
authors.affiliation: Department of Molecular Virology, Immunology & Medical Genetics, Columbus, OH 43210, USA; Institute of Behavioral Medicine Research, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Glaser
authors.affiliation: Institute of Behavioral Medicine Research, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Sheridan
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Nelson
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001831:Body Temperature / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002908:Chronic Disease; D004435:Eating / Q000502:physiology; D004926:Escherichia coli; D004854:Herpesvirus 4, Human / Q000235:genetics*; D007859:Learning Disabilities / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000503:physiopathology*; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012149:Restraint, Physical / Q000009:adverse effects*; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D014764:Viral Proteins; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase
keywords: Chronic restraint stress; Epstein–Barr virus; Learning and memory; Sickness response