# Epstein-Barr Virus Driven Tonsillar Versus Peripheral B-cell One-Carbon Metabolic Network Remodeling

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $528,226

## Abstract

Abstract
Epstein-Barr virus (EBV) is the etiologic agent of infectious mononucleosis, is the major trigger
for multiple sclerosis and is associated with a range of lymphoproliferative disorders and
carcinomas. EBV is spread between hosts through the oral cavity, where it crosses epithelial
barriers to infect naïve B cells in tonsil lymphoepithelial tissue. Primary EBV infection and much
of the EBV lifecycle is centered in the oropharynx, which are persistently colonized. Yet, much
remains to be learned about virus/host interactions that govern the oral cavity EBV lifecycle.
According to the EBV germinal center model, EBV uses latency programs to navigate the B-cell
compartment, initially driving B-cell activation and growth via the pre-latency, latency IIb and
latency III programs. Incompletely understood cues in tonsil and related lymphoid tissues are
thought to switch the EBV program to latency IIa in germinal centers. Subsequent differentiation
into memory B-cells, the reservoir for lifelong EBV infection, give rise to the latency I program,
comprised of a single EBV latency gene, EBNA1. However, this has remained difficult to model
and limited information is available about EBV/host interactions in the tonsil microenvironment.
This lifecycle is highly associated with EBV-driven malignancies, with a heavy disease burden in
craniofacial regions, including Burkitt lymphoma and nasopharyngeal carcinoma. However,
much remains to be learned about how EBV rewires host cell one-carbon (1C) metabolism to
support key aspects of the viral lifecycle in tonsillar versus peripheral blood B-cells. We
therefore used metabolomic, proteomic and CRISPR genetic approaches to identify a central
role for interconnecting methionine and folate 1C metabolism pathways in support of EBV-
driven B-cell transformation and the viral lifecycle. Our central hypothesis is that EBV latency
programs subvert multiple levels of interconnecting methionine and folate metabolism cycles to
perform non-redundant functions critical for the viral B-cell lifecycle in tonsil versus peripheral
blood compartments. Using novel primary human B-cells and tonsil tissue models, our Specific
Aims are therefore to: 1) Identify key mechanisms by which EBV drives newly infected tonsil
and peripheral blood B-cell methionine dependency; (2) Identify key mechanisms by which
methionine metabolism drives newly infected tonsil and peripheral blood Epstein-Barr nuclear
antigen expression and signaling; (3) Characterize key EBV latency gene-induced methionine
and folate metabolism roles in tonsil peripheral blood B-cell redox defense. Our studies will
provide novel insights into crosstalk between immunometabolism, viral latency gene programs
and redox defense critical for the EBV lifecycle, with relevance to novel therapeutic approaches.

## Key facts

- **NIH application ID:** 10905329
- **Project number:** 1R01DE033907-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Benjamin Elison Gewurz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $528,226
- **Award type:** 1
- **Project period:** 2024-05-06 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905329

## Citation

> US National Institutes of Health, RePORTER application 10905329, Epstein-Barr Virus Driven Tonsillar Versus Peripheral B-cell One-Carbon Metabolic Network Remodeling (1R01DE033907-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10905329. Licensed CC0.

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