Plasmodium falciparum (Pf) malaria and Epstein-Barr Virus (EBV) co-infections in children residing in malaria holoendemic areas have been linked to an increased risk of an EBV-associated cancer called endemic Burkitt lymphoma (eBL). Most African children are infected with EBV before 1 year of age, yet this B-cell cancer does not occur until years later. It has been postulated that repeated episodes of malaria ?suppress? immunity to EBV, creating a permissive environment for eBL pathogenesis. However, the mechanisms responsible are not fully understood. Our prior studies found that malaria-exposed children had pathologically high EBV loads; ?? nave-like EBV-specific CD8+ T cells with diminished effector functions; unconventional, innate-like CD8+ T cells that expressed Granzyme B in lieu of IFN- ; and an expansion of ?chronic-infection induced? CD56neg Natural Killer (NK) cells with impaired cytotoxicity. Thus, we have identified proximate immunologic alterations that allow unrestrained EBV replication and eBL tumorigenesis. In this renewal application, we will our central hypothesis that malaria-induced immunoregulatory mechanisms restrain T cell cytotoxicity against EBV-infected B cells and eBL tumors. This will be tested by the following Specific Aims.
Aim 1. Determine ?? if repeated Pf-malaria infections, known to induce EBV reactivation, lead to increased inhibitory co- receptor expression on EBV-specific CD8+ ? T cells. Expression of TIGIT, PD1, CTLA4, LAG3, TIM3, CD160, 2B4, KLRG1, BTLA, on T cell subsets will be measured by flow cytometry. Exhaustion versus cytotoxicity signatures will be further defined with single cell RNA sequencing, and functional capacity tested in vitro by cytotoxic T lymphocyte (CTL) assays using EBV-transformed lymphoblastoid cell lines (LCLs).
Aim 2. Determine if repeated Pf-malaria infections induce IL-10 producing CD4+ or CD8+ T cells that exert an immune-regulatory effect on EBV-specific T cells. The frequency of IL-10 secreting Foxp3neg regulatory CD25+, CD4+, Tr1 cells (CD49b+, LAG3+, CD226+/DNAM1+), Treg-of-B cells (LAG3+, ICOS+, PD1+, GITR+, OX40+) and CD8+ CD25neg Foxp3neg T cells will be measured by flow cytometry and RNAseq to distinguish them from classical CD4+Fox??p??3+ regulatory T cells (Tregs). CTL assays will determine the impact of IL-10 cytokine family members on CD8+ T cell cytotoxicity, in vitro.
Aim 3. Determine if repeated Pf-malaria ???? infections influence the frequency of T to NK cell subsets and how their relative ratios impact ???? cytotoxicity to eBL tumors. The frequency of T and NK cell subsets will be evaluated by flow cytometry and associated with malaria exposure. Cytotoxicity of T and NK cell subsets will be quantified in vitro against BL tumors, including our newly established patient-derived eBL cell lines. Ligand-receptor blocking experiments will evaluate the relative contribution of each subset to overall cytotoxicity. Understanding how malaria influences the human immunologic landscape, especially in children, will allow us to explore interventions that modulate regulatory mechanisms while maintaining protective immunity to EBV.

Public Health Relevance

This proposal focuses on understanding the role of malaria in diminishing T cell immunity to Epstein-Barr Virus in children. These two infections interact to increase the risk of endemic Burkitt lymphoma, which is the most common childhood cancer in Equatorial Africa. Results from this study will help us understand how to prevent this cancer and to design better treatments to improve survival for these children.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
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Daschner, Phillip J
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University of Massachusetts Medical School Worcester
Anatomy/Cell Biology
Schools of Medicine
United States
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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:
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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 :
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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
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

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