Malaria and EBV Studies
- Characterize the immuno-profiles of Pf associated with eBL;
- Characterize the genetic complexity (swarms) of Pf genotypes in eBL cases.
- Immunoprofiles that are associated with elevated eBL risk;
- Co-factors associated with poor control of EBV, focusing on systemic magnesium;
- EBV variants associated with eBL.
Although deleterious chromosomal translocations that place coding regions of c-MYC under regulatory control of immunoglobulin enhancer elements are considered primary genetic events in BL, Epstein-Barr virus (EBV) and Plasmodium falciparum (Pf) malaria are considered important secondary co-factors that influence the geographic distribution of BL. These pathogens may influence endemic Burkitt Lymphoma (eBL) risk by increasing the genetic instability in B cells or increasing the number of abnormal B cells circulating in exposed individuals.
Malaria studies in EMBLEM aim to use serological and molecular markers of Pf infection to define at risk populations for BL, determine whether BL risk is related to particular malaria antigens or to a swarm of antigens. These studies take advantage of recent innovations in new generation sequencing technologies that allow molecular barcoding of Pf parasites to define swarms of infection and proteomic technologies that allow antibodies to malaria virulence proteins to be studies with great sensitivity and specificity.
The immunoprofile studies address the hypothesis of whether eBL cases are more likely to serologically recognize antigens associated with severe malaria and, if so, are they likely to have a stronger and more diverse repertoire of reactivity to Pf virulent proteins. The studies focus on the Pf erythrocyte membrane protein 1 (PfEMP1), whose expression has been linked to life-threatening malaria complications. Four main PfEMP1 types have been characterized, which include: VAR2CSA PfEMP1, which binds to the placental chondroitin sulfate A (CSA) to cause malaria in pregnancy. Three cysteine-rich interdomain region (CIDR)α1, CIDRα2-6, or CIDRβ/δ/γ domains, which bind to endothelial protein C receptor [EPCR], CD36, and receptors yet to be characterized. EPCR-binding PfEMP1 is detected in parasites associated with severe malaria, whereas CD36-binding PfEMP1 parasites are frequently detected in parasites causing mild or asymptomatic malaria infections. Careful serological studies will provide further insights regarding a malaria antigen encountered by eBL cases and the nature and adequacy of the associated immune response.
The molecular barcode studies address the hypothesis of whether eBL cases when infected by Pf parasites, are more likely to lead to more complex (swarms) or mono- or oligo-clonal infection. It is currently unknown whether the risk of eBL is related to total parasite load or high antigen diversity regardless of parasite load. Our previous studies found that eBL age-specific patterns were varied concomitantly with complexity of infection (swarms) rather than parasite density. Our studies focus on novel Pf molecular barcode developed by the Broad Institute to characterize monoclonal versus polyclonal infections.
- Associations between IgG reactivity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens and Burkitt lymphoma in Ghana and Uganda case-control studies
- Relationship between Plasmodium falciparum malaria prevalence, genetic diversity and endemic Burkitt lymphoma in Malawi
- Burkitt lymphoma expresses oncofetal chondroitin sulfate without being a reservoir for placental malaria sequestration
- Endemic Burkitt lymphoma is associated with strength and diversity of Plasmodium falciparum malaria stage-specific antigen antibody response
- Antibodies reactive to Plasmodium falciparum serine repeat antigen in children with Burkitt lymphoma from Ghana
- African Burkitt lymphoma: age-specific risk and correlations with malaria biomarkers
EBV is a class 1 carcinogen for BL, but we currently lack a good understanding of the mechanism and of specific characteristics associated with elevated risk of eBL among populations infected with EBV from birth. Our work on EBV aims to associate identified immune responses to a panel of EBV antigens that may be predictive of eBL. This work uses recently developed EBV protein arrays to probe immune responses in well-characterized cohorts with elevated risk of EBV. In addition, our work is employing next generation sequencing methods of EBV for discovery of EBV variants associated with eBL. Finally, we are interested in potentially modifiable co‑factors of EBV infection, focusing on systemic magnesium. The magnesium hypothesis springs from Dr. Michael Lenardo's (Laboratory of Immunology at NIAID) discovery of a primary immunodeficiency syndrome named X-linked immunodeficiency with magnesium defect, uncontrolled EBV infection, and neoplasia (XMEN). XMEN results from magnesium deficiency due to genetic abnormalities in MAGT1. Our work seeks to determine whether systemic magnesium deficiency from any cause may be associated with poor EBV control and elevated eBL risk.
- Frequency of EBV LMP-1 Promoter and Coding Variations in Burkitt Lymphoma Samples in Africa and South America and Peripheral Blood in Uganda
- Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations
- Plasma magnesium is inversely associated with Epstein-Barr virus load in peripheral blood and Burkitt lymphoma in Uganda