Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection.
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2017-04-20
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Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.
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Price, Alexander M, Joanne Dai, Quentin Bazot, Luv Patel, Pavel A Nikitin, Reza Djavadian, Peter S Winter, Cristina A Salinas, et al. (2017). Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection. Elife, 6. 10.7554/eLife.22509 Retrieved from https://hdl.handle.net/10161/14611.
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Scholars@Duke
Kris Cameron Wood
Our laboratory uses genomic and pharmacological approaches to understand how tumor dependencies are shaped by cell intrinsic factors, environmental factors, and drug treatments during the dynamic process of tumor evolution. To learn more, please visit our laboratory website: https://woodlabduke.com/.
Micah Alan Luftig
The Luftig laboratory studies viruses that cause cancer with an overarching goal of defining the basic molecular mechanisms underlying pathogenesis and leveraging these findings for diagnostic value and therapeutic intervention. Our work primarily focuses on the common herpesvirus, Epstein-Barr virus (EBV). This virus latently infects virtually all adults worldwide being acquired early in life. In the immune suppressed, EBV promotes lymphomas in the B cells that it naturally infects. However, EBV can also infect epithelial cells and other lymphocytes contributing to human cancers as wide-ranging as nasopharyngeal and gastric carcinoma to aggressive NK/T-cell, Burkitt, and Hodgkin lymphomas. Overall, EBV contributes to approximately 2% of all human cancers worldwide leading to nearly 200,000 deaths annually.
We use cutting-edge, cross-disciplinary and highly collaborative approaches to characterize the temporal dynamics and single cell heterogeneity of EBV infection. With these strategies, we aim to discover fundamental molecular circuits underlying transcriptional control, viral manipulation of host signaling pathways, and metabolic regulation that collectively influence infected cell fate decisions. By understanding the nature of viral control of infected host cells, we are also well positioned to discover vulnerabilities in EBV-associated diseases and characterize new therapeutic interventions in cell-based and pre-clinical animal models.
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