# Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $640,406

## Abstract

Our long-term goal is to understand how the development of B-cell lymphomas is influenced by infection
and the antigen specificity of their surface-bound B-cell receptors (BCR). The objective in this proposal is to
understand how Pf and EBV cooperate to promote and maintain eBL. It is our central hypothesis that Pf infection
promotes EBV-mediated B-cell proliferation, Pf antigens are recognized by the EBV-infected BCR promoting the
BL-characteristic IgH/c-Myc translocation, and that eBL tumor maintenance is supported by EBV regulation of
tumor cell survival and Pf alteration of T-cell immunity. Our central hypothesis is premised on strong rationale
from the literature and our preliminary data characterizing the interplay between EBV and Pf in eBL. First, EBV
is clonally present in eBL cells suggesting both an early role in tumorigenesis and a requirement in tumor
maintenance. Second, malaria holoendemic areas are known hotspots for eBL where rates are as much as 100-
fold higher than in low/no malarial regions. Third, EBV infection of B cells potently activates expression of
activation-induced cytidine deaminase (AID), which is critical for BL-characteristic Ig/c-Myc translocations. While
the EBV latent protein EBNA2 opens B-cell chromatin upstream of the c-Myc gene promoting expression, it also
suppresses IgH transcription. Since IgH transcription is required for AID to gain access to the IgH locus and is
required for the IgH/c-Myc translocation, an additional factor must be affecting EBV-infected cells allowing this
translocation to occur. We hypothesize that Pf provides this factor in the form of antigen recognized by the EBV-
infected B-cell surface Ig. We propose that Pf infections provide both mitogenic signals to promote B-cell
proliferation as well as critical antigens driving AID-mediated BCR affinity maturation, which aberrantly leads to
the IgH/c-Myc translocation. Following the translocation, eBL tumors must withstand strong pressure from the
immune system against both the virus and tumor neoantigens. Our recent work indicates a strong suppressive
influence of Pf infection in vivo on CD8 T-cell recognition of EBV and eBL that we propose supports tumor
maintenance. The rationale for this proposal is that understanding the molecular mechanisms of eBL initiation
and pathogenesis vis-à-vis viral and parasite co-infection will provide us with a platform for understanding the
role of BCR specificity in B lymphomagenesis as well as how Pf infection influences immune surveillance to
support tumor maintenance. We plan to test our central hypothesis by pursuing the following three specific aims:
1) to determine the role of P. falciparum in collaborating with EBV to induce B-cell proliferation and tumorigenesis,
2) to determine the role of P. falciparum antigens as the critical trigger of the IgH/c-Myc translocation in eBL, and
3) to determine the interplay between EBV and P. falciparum immune alterations in eBL tumor maintenance.

## Key facts

- **NIH application ID:** 10459337
- **Project number:** 5R01CA234348-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Micah Alan Luftig
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $640,406
- **Award type:** 5
- **Project period:** 2019-08-14 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459337

## Citation

> US National Institutes of Health, RePORTER application 10459337, Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis (5R01CA234348-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459337. Licensed CC0.

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