The syndemic interaction between Plasmodium falciparum malaria and Epstein-Barr virus (EBV) that predispose children to endemic Burkitt lymphoma (eBL), an EBV-associate B cell tumor and the most prevalent pediatric cancer in Equatorial Africa is not completely understood. Due to the prolonged period between primary EBV infection, compounded by repeated malaria infections, and the presentation of eBL later in childhood, longitudinal studies are required in order to fully understand the cumulative impact of malaria on shaping T cell immunity to EBV in the etiology of eBL. Therefore, this proposal aims to test our central hypothesis that malaria adversely influences the differentiation and survival o EBV-specific T cell responses which results in the loss of T cell control over EBV, thereby setting the stage for lymphomagenesis. This hypothesis will be tested by the following Specific Aims.
Aim 1. Determine if the prevalence of T memory stem cells (TSCM) correlates with EBV control in children and if EBV-specific TSCM isolated from children have the capacity to expand when instructed by IL-15 and IL-7. CD4+ and CD8+ T cell subsets will be characterized by expression of memory markers (CD45RA/RO, CCR7, CD27, CD127, and CD95) and functionality (IL-2, TNF-?, IFN-?, CD107a) in a retrospective cohort study of children with divergent malaria exposure histories who have been categorized as EBV controllers or non-controllers. IL-7 and IL-15 stimulation will be used to evaluate the expansion potential of TSCM (CD45RA+, CCR7+, CD27+, CD95+).
Aim 2. Evaluate the relationship between malaria-associated pro-inflammatory (IL-12, IL-23, IL-31, IL-33) and regulatory (IL-27, IL-35, IL-37) cytokine levels and the expression of transcription factors regulating T cell differentiation that correlate with EBV control in children. We hypothesize that malaria-induced changes in the cytokine environment will influence expression of transcription factors (IRF4, T-bet, Eomes, Bcl6 and TCF1) and thus influence T cell survival.
Aim 3. Determine if malaria co-infection during primary EBV infection has a negative impact on the development of EBV-specific T cells associated with viral control and if this phenotype is progressively altered after repeated malaria infections. A newly established prospective infant cohort study will allow us to capture pivotal events during primary EBV infection to determine whether concurrent and/or cumulative malaria co-infections alter the cytokine milieu and thereby influence the quality and survival of EBV- specific T cells. Information gained from studying T cell memory in children and the immune regulatory microenvironment governing T cell fate will provide novel mechanistic insights into when and how malaria alters EBV immunosurveillance. Improved understanding of the complexity of T cell regulation and survival that renders children co-infected with EBV and malaria at increased risk for eBL will facilitate the development of preventive and therapeutic strategies for this common childhood cancer.

Public Health Relevance

This proposal focuses on the impact of Plasmodium falciparum malaria on the development and maintenance of functional EBV-specific T cell immunity in Kenyan children who experience these co-infections early in life and are therefore at increased risk for developing endemic Burkitt lymphoma, the most prevalent pediatric cancer in Equatorial Africa. Understanding the syndemic relationship between malaria and EBV co-infections will provide novel insights into when and how malaria alters EBV immunosurveillance. Results from this study will provide a framework for interventions aimed at preventing eBL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA189806-01A1
Application #
8767080
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Daschner, Phillip J
Project Start
2014-07-10
Project End
2019-05-31
Budget Start
2014-07-10
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$556,494
Indirect Cost
$180,711
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
Forconi, Catherine S; Cosgrove, Cormac P; Saikumar-Lakshmi, Pryia et al. (2018) Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas. Blood Adv 2:1101-1114
Oduor, Cliff I; Movassagh, Mercedeh; Kaymaz, Yasin et al. (2017) Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma. Front Microbiol 8:501
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 :
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
Parsons, Emily; Otieno, Juliana A; Ong'echa, John Michael et al. (2016) Regulatory T Cells in Endemic Burkitt Lymphoma Patients Are Associated with Poor Outcomes: A Prospective, Longitudinal Study. PLoS One 11:e0167841
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
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

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