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.
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.
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