Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection
- Duke University School of Medicine, United States
- Imperial College London, United Kingdom
- Harvard Medical School, United States
- University of Wisconsin School of Medicine and Public Health, United States
- Duke University, United States
Abstract
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 NFB 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/NFB 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.
Data availability
-
EBNA2 ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE29498).
-
The NF-kB genomic landscape in lymphoblastoid B-cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE55105).
-
EBNA3C ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE52632).
-
EBNA3A ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE59181).
-
Histone modifications in LCLs (ENCODE)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE29611).
-
TF binding sites in LCLs (ENCODE)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE31477).
Article and author information
Author details
Funding
National Cancer Institute (R01-CA140337)
- Micah A Luftig
American Cancer Society (RSG-13-228-01-MPC)
- Micah A Luftig
Wellcome (099273/Z/12/Z)
- Quentin Bazot
- Martin J Allday
National Institute for Dental and Cranofacial Research (R01-DE025994)
- Joanne Dai
- Micah A Luftig
National Institute for Allergy and Infectious Diseases (5P30-AI064518)
- Micah A Luftig
National Cancer Institute (F31-CA180451)
- Alexander M Price
National Institute for Dental and Cranofacial Research (R01-DE023939)
- Eric C Johannsen
National Institute for Allergy and Infectious Diseases (T32-AI078985)
- Reza Djavadian
National Cancer Institute (R01-CA129974)
- Anthony Letai
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Price et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,678
- views
-
- 726
- downloads
-
- 63
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection
eLife 6:e22509.
https://doi.org/10.7554/eLife.22509
Further reading
-
- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
-
- Cancer Biology
- Immunology and Inflammation
In this study, we present a proof-of-concept classical vaccination experiment that validates the in silico identification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNA-seq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responses in mice following classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies.
