Abstract
The Epstein-Barr virus (EBV), which is a ubiquitous γ-herpesvirus, establishes a latent infection in more than 90% of the global adult population. EBV-associated malignancies have increased by 14.6% over the last 20 years, and account for approximately 1.5% of all cancers worldwide and 1.8% of all cancer deaths. However, the potential involvement/contribution of lytic proteins to the pathophysiology of EBV-associated cancers is not well understood. We have previously demonstrated that the EBV-deoxyuridine triphosphate nucleotidohydrolase (dUTPase) modulates innate and adaptive immune responses by engaging the Toll-Like Receptor 2 (TLR2), which leads to the modulation of downstream genes involved in oncogenesis, chronic inflammation, and in effector T-cell function. Furthermore, examination of serum samples from diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia patients revealed the presence of increased levels of anti-dUTPase antibodies in both cohorts compared to controls with the highest levels (3.67-fold increase) observed in DLBCL female cases and the lowest (2.12-fold increase) in DLBCL males. Using computer-generated algorithms, dUTPase amino acid sequence alignments, and functional studies of BLLF3 mutants, we identified a putative amino acid motif involved with TLR2 interaction. These findings suggest that the EBV-dUTPase: TLR2 interaction is a potential molecular target that could be used for developing novel therapeutics (small molecules/vaccines).
Highlights
These findings suggest that the Epstein-Barr virus (EBV)-deoxyuridine triphosphate nucleotidohydrolase (dUTPase): Toll-Like Receptor 2 (TLR2) interaction is a potential molecular target that could be used for developing novel therapeutics
We have demonstrated that the dUTPases encoded by the human herpesviruses represent a new class of pathogen-associated molecular pattern (PAMP) proteins that have novel immuno-regulatory and neuro-regulatory functions, which may contribute to the pathophysiology of diseases caused
Examination of serum samples from diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) patients revealed the presence of increased anti-dUTPase neutralizing antibodies in both cohorts compared to controls with the highest levels (3.67-fold increase) observed in diffuse large B cell lymphoma (DLBCL) female cases and the lowest (2.12-fold increase) in the DLBCL males
Summary
Epstein-Barr virus, which is a γ herpesvirus, is a ubiquitous virus that establishes a latent infection in over 90% of the global adult population. DLBCL is a heterogeneous disease that is classified based on micro-array-based gene expression profiling as germinal center B-cell like (GCB) DLBCL or activated. B-cell-like (ABC) DLBCL [2]. A small percentage (10–20%) of DLBCLs are EBV-genome positive and such tumors are usually classified in the ABC DLBCL group [3]. While EBV-genome positive tumors were originally discovered in older (>50 years of age) immunocompetent individuals [4,5,6,7,8], they have recently been reclassified to EBV+ DLBCL-NOS due to the increased occurrence of EBV+ DLBCL in younger immunocompetent patients [9]. EBV is an independent factor that adversely affects risk and/or survival among patients with DLBCL [5,7].
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