title: EBV-encoded dUTPase induces immune dysregulation: Implications for the pathophysiology of EBV-associated disease.
abstract: Epstein-Barr virus (EBV) encodes for several enzymes that are involved in viral DNA replication. There is evidence that some viral proteins, by themselves, can induce immune dysregulation that may contribute to the pathophysiology of the virus infection. In this study, we focused on the EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and present the first evidence that the dUTPase is able to induce immune dysregulation in vitro as demonstrated by the inhibition of the replication of stimulated peripheral blood mononuclear cells (PBMCs) and the upregulation of several proinflammatory cytokines including TNF-alpha, IL-1beta, IL-8, IL-6, and IL-10 produced by unstimulated PBMCs treated with purified EBV-encoded dUTPase. Depletion of CD14-positive cells (monocytes) eliminated the cytokine profile induced by EBV dUTPase treatment. The data support the hypothesis that at least one protein of the EBV early antigen complex can induce immune dysregulation and may be involved in the pathophysiology of EBV-associated disease.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, 333 W. 10th Avenue, Columbus, OH 43210, USA. glaser.1@osu.edu
authors.forename: Ronald
authors.initials: R
authors.lastname: Glaser
authors.forename: Monica L
authors.initials: ML
authors.lastname: Litsky
authors.forename: David A
authors.initials: DA
authors.lastname: Padgett
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.forename: Eric V
authors.initials: EV
authors.lastname: Yang
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Peir-En
authors.initials: PE
authors.lastname: Yeh
authors.forename: Kari B
authors.initials: KB
authors.lastname: Green-Church
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Marshall V
authors.initials: MV
authors.lastname: Williams
mesh_terms: D000595:Amino Acid Sequence; D016207:Cytokines / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000503:physiopathology* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000201:enzymology* / Q000472:pathogenicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000821:virology; D011755:Pyrophosphatases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase