Epstein-Barr virus (EBV) was discovered over 50 years ago because of research into the etiology of endemic Burkitt lymphoma (BL). BL remains one of the most common and still frequently fatal pediatric cancers in sub- Saharan Africa. A second critical co-factor in the etiology of BL is repeated infection with Plasmodium falciparum (Pf) malaria. The exact cellular and molecular events that link these two pathogens to increase the risk for BL and drive the c-myc translocation characteristic of BL remain to be elucidated. Without this information, our understanding of the etiology of BL, a cancer called the Rosetta Stone for deciphering viral oncogenesis, remains incomplete. The overall goal of our research is to understand why children living in malaria endemic regions are at high risk for BL. Based on our studies in Kenya where we found children living in a malaria endemic region were infected with EBV early in life, had higher EBV viral loads over time and that malaria exposure has an independent effect on increasing EBV viral loads in children. Combined, these data point to an important role for malaria infection in dysregulating EBV latency. To account for the effects of malaria on EBV-infected B cells, we are proposing a variation of the GC model, termed the ?Dysequilibrium model of EBV persistence.? In our model, the excess of heme released during malaria infection binds to the B cell transcription factor, Bach2 suppressing its activity. Release of Bach2 mediated suppression allows Blimp1 to orchestrate plasma cell differentiation. EBV would reactivate in terminally differentiated plasma cells resulting in viremia and an elevated population of secondarily infected B cells. An increased frequency of EBV- infected B cells in and of itself is not necessarily problematic but we have also observed high levels of the enzyme?activation induced deaminase (AID)?in peripheral blood mononuclear cells (PBMC) in children living in a malaria endemic region and dysregulation of AID expression in B cell subsets during acute malaria. The critical molecular event that defines BL is the translocation of the c-myc oncogene into the immunoglobulin heavy chain locus, an event mediated by AID. Moreover, we show in our preliminary data that BAFF synergizes with EBV to induce AID. Thus, the elevated population of latently infected B cells would be induced to express AID increasing the risk for the c-myc translocation. Utilizing lymphocytes analyzed ex vivo, EBV+ B cell lines, and in pediatric clinical samples from our field site in Kisumu, Kenya, we will test two key predictions based on our model. First, that release of excessive heme by lysis of RBC during malaria results in EBV reactivation in plasma cells and expansion of the latently infected B cell pool. Second, that increases in BAFF during malaria results in aberrant AID expression in EBV-positive B cells. Dysregulation of EBV persistence likely contributes not only to BL but also to other EBV-associated malignancies where co-factors are required for emergence of disease. Lessons learned from studying the etiology of BL could potentially be used for understanding the etiology of other EBV associated malignancies.

Public Health Relevance

Endemic Burkitt's lymphoma (BL), the most prevalent childhood cancer in Equatorial Africa, is a rapidly growing B-cell malignancy that is ultimately fatal if untreated. The knowledge gained by this study will improve the understanding of the etiology of endemic BL which will ultimately allow for the design of tools aimed at the prevention of BL.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI141531-02
Application #
10070567
Study Section
Virology - B Study Section (VIRB)
Program Officer
Dyall, Julie
Project Start
2019-12-12
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045