The long-term goal of this proposal is to understand the etiology of endemic Burkitt's lymphoma (eBL), the most prevalent pediatric cancer in equatorial Africa. Epidemiologic studies of eBL indicate a strong association with Plasmodium falciparum malaria and Epstein-Barr virus (EBV) infections early in childhood. Although it is not known how malaria-EBV interactions increase the risk of eBL, it has been suggested that malaria-mediates suppression of EBV-specific T cell immunity. Our central hypothesis is that holoendemic malaria impairs the development and maintenance of EBV-specific effector and central memory T cell immunity. We hypothesize that two, though not mutually exclusive, mechanisms are responsible for the observed suppression of EBV immunity in African children: 1) Repeat/chronic malaria infections result in high EBV viral load, that in turn induce `CD45RA+ re-expressing'effector memory CD8+ T cell (TEMRA) which display immediate IFN-3 expression but are more susceptible to apoptosis than effector memory T cells (TEM) and/or 2) Repeat/chronic malaria infections diminish EBV-specific T cell responsiveness to homeostatic cytokines (i.e. IL-15 and IL-7). This hypothesis will be tested by examination of EBV-specific immunity in healthy Kenyan children with divergent malaria exposure histories and of eBL children.
The specific aims will test the following hypotheses:
Aim 1. Cumulative exposure to malaria and high EBV viral load determine the frequencies of EBV- specific CD8+ TEMRA. EBV-specific CD8+ T cells will be quantified using HLA Class I tetramers and T cell subsets defined as central memory, TCM (CD45RA-CD62L+CCR7+);effector memory, TEM (CD45RA-CD62L- CCR7-);and RA re-expressing effector memory, TEMRA (CD45RA+CD62L-CCR7-). EBV-specific T cell IFN-3 production, TCR V2 usage and proliferation by carboxyfluorescein succinimidyl ester (CFSE) dilution will be compared between the three groups of children.
Aim 2. IL-15 and/or IL-7 responsiveness of EBV-specific memory T cells is impaired in children with chronic malaria exposure and in children with eBL. IL-15R1 and IL-7R1 surface expression, CFSE proliferation of EBV-specific T cells in response to cognate antigen with and without IL-15 or IL7, and responsiveness measured by STAT5 phosphorylation will be compared between the three groups of children.
Aim 3. Cumulative exposure to malaria and high EBV viral load determine the frequencies of EBNA1- specific memory T cell subsets. Overlapping peptide libraries of EBNA1 will be used to identify EBNA1- specific IFN-3 expressing and proliferating memory T cell subsets. The precursor numbers of proliferating and the frequency of IFN-3 producing EBNA1-specific T cells will be compared between the three groups of children. Given that most knowledge regarding EBV T cell immunity is based on examination of asymptomatic adults or those who have had infectious mononucleosis, studies proposed here will provide novel information with respect to the evolution of EBV immunity in healthy children as well as those with eBL.

Public Health Relevance

Burkitt lymphoma (BL) is a prevalent pediatric cancer. Understanding BL etiology will aid in the prevention of this aggressive B cell malignancy. Results from this research will ultimately improve the prospects for successful cancer immunotherapies and vaccine development for EBV-associated lymphomas such as BL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134051-04
Application #
7800429
Study Section
Special Emphasis Panel (ZRG1-IDM-Q (02))
Program Officer
Howcroft, Thomas K
Project Start
2008-06-05
Project End
2013-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$465,952
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Falanga, Yves T; Frascoli, Michela; Kaymaz, Yasin et al. (2017) High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells. JCI Insight 2:
Kaymaz, Yasin; Oduor, Cliff I; Yu, Hongbo et al. (2017) Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences. Mol Cancer Res 15:563-576
Oduor, Cliff I; Kaymaz, Yasin; Chelimo, Kiprotich et al. (2017) Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma. BMC Cancer 17:761
Kaymaz, Yasin; Oduor, Cliff I; Yu, Hongbo et al. (2017) Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-specific Differences. Mol Cancer Res :
Moormann, Ann M; Bailey, Jeffrey A (2016) Malaria - how this parasitic infection aids and abets EBV-associated Burkitt lymphomagenesis. Curr Opin Virol 20:78-84
Reynaldi, Arnold; Schlub, Timothy E; Piriou, Erwan et al. (2016) Modeling of EBV Infection and Antibody Responses in Kenyan Infants With Different Levels of Malaria Exposure Shows Maternal Antibody Decay is a Major Determinant of Early EBV Infection. J Infect Dis 214:1390-1398
Reynaldi, Arnold; Schlub, Timothy E; Chelimo, Kiprotich et al. (2016) Impact of Plasmodium falciparum Coinfection on Longitudinal Epstein-Barr Virus Kinetics in Kenyan Children. J Infect Dis 213:985-91
Bowman, Natalie M; Juliano, Jonathan J; Snider, Cynthia J et al. (2016) Longevity of Genotype-Specific Immune Responses to Plasmodium falciparum Merozoite Surface Protein 1 in Kenyan Children from Regions of Different Malaria Transmission Intensity. Am J Trop Med Hyg 95:580-7
Buckle, Geoffrey; Maranda, Louise; Skiles, Jodi et al. (2016) Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study. Int J Cancer 139:1231-40
Mulama, David H; Bailey, Jeffrey A; Foley, Joslyn et al. (2014) Sickle cell trait is not associated with endemic Burkitt lymphoma: an ethnicity and malaria endemicity-matched case-control study suggests factors controlling EBV may serve as a predictive biomarker for this pediatric cancer. Int J Cancer 134:645-53

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