The role of EBNA3A in the survival of Epstein-Barr Virus-infected tonsillar B cells

Duke University, Durham NC

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Abstract

PROJECT SUMMARY More than 95% of the global adult population is infected with Epstein-Barr virus (EBV). Primary infection occurs when EBV infects a B cell of the oral cavity, and while infection is asymptomatic for immune-competent hosts, EBV can drive B-cell lymphoma development in immune-suppressed individuals who are infected with HIV or undergoing organ transplant. As a result, understanding how EBV establishes a latent infection and how this contributes to lymphomagenesis is critical for identifying potential therapeutic targets. In an in vitro model of EBV-mediated transformation, our lab has recently found that the viral nuclear protein EBNA3A mediates two temporally distinct survival strategies at the mitochondria. While uninfected B cells depend on the anti-apoptotic BCL-2 protein for survival, EBNA3A upregulates MCL-1 in early-infection and BFL-1 in late-infection. Specifically, EBNA3A promotes MCL-1 accumulation at the mitochondria and BFL-1 transcription in the nucleus. Without EBNA3A, EBV-infected B cells fail to upregulate MCL-1 and BFL-1 activity and are sensitive to the chemotherapeutic ABT-737, which induces apoptosis by inhibiting the anti-apoptotic proteins BCL-2, BCL-XL, and BCL-W. Therefore, the purpose of this proposal is to determine the mechanism by which EBNA3A regulates MCL-1 and BFL-1 in EBV-infected tonsillar B-cell survival. We have also observed changes in anti-apoptotic dependency in maturing B cells from human tonsillar tissue, in which BCL2-dependent naïve B cells become MCL1-dependent when undergoing the germinal center reaction. Thus, my overall hypothesis is that EBV infection mimics B cell maturation to promote survival and that shifts in anti-apoptotic dependency are important for establishing a long-lived latent infection. In Aim 1, I will define the role of EBNA3A in the expression of BAG3 and USP9X in regulating MCL-1 accumulation at the mitochondria and resistance to ABT-737. In Aim 2, I will elucidate the mechanism by which EBNA3A cooperates with RelA in regulating chromatin architecture to promote BFL-1 transcription. Completion of this study will enhance our understanding of how EBNA3A regulates apoptosis over the course of EBV infection and provide critical information for identifying new therapeutic strategies for EBV-associated lymphomas and elimination of latently-infected B cells.