Epstein-Barr virus (EBV) establishes a lifelong persistent infection in the resting memory B cells of virtually all humans, yet is associated with three forms of lymphoma: Burkitt's, immunoblastic and Hodgkin's. The mechanism of persistent infection is described by the germinal center (GC) model, developed during previous funding periods of this grant, whereby EBV converts newly infected B cells into resting memory cells via the GC reaction. The model also provides an explanation for the origin of the associated lymphomas. In this proposal we will address the origins of endemic Burkitt's lymphoma (eBL), the most common tumor amongst African children. eBL arises from the GC and has three characteristic features: latent EBV infection, translocation of the c-myc oncogene and concordance with holoendemic P. falciparum infection. Currently, we lack a comprehensive explanation for the role of EBV and malaria in eBL pathogenesis. We hypothesize that eBL arises from two converging events in the GC. The first is hyper-activation of AID (activation associated cytidine deaminase) by malarial antigens. AID mediates somatic hypermutation and class switch recombination in the GC, but also causes c-myc translocations. The second is that the immunosuppressive properties of malaria lead to higher throughput of EBV infected GC B cells. This increases the risk that the translocation occurs in a GC B cell that can tolerate it du to the presence of EBV. We predict, therefore, that GCs from individuals with chronic malaria infection will have elevated levels of EBV infected cells, AID expression, AID mediated mutations and c-myc translocations. To test this we will show that: 1. P. falciparum activates AID in vitro. Tonsil B cells will be cultured with various AID agonists combined with parasite preparations including whole extracts from infected RBCs, intact infected RBCs, purified parasites, the parasite by product hemozoin (known TLR ligand) and parasites lacking PfEMP1 (known BCR ligand). 2. the levels of AID expression (RT-PCR and Western blotting) are elevated in GC B cells from an area of holoendemic malaria (Ghana) compared to controls from individuals in the same area under long-term anti-malarial treatment or from areas that lack P. falciparum (Boston and Brazil). 3. the levels of EBV infected cells in the GCs of tonsils from Ghana are elevated and determine if this is associated with deregulation of EBV persistence (flow cytometry, microdissection of whole GCs and single infected cells combined with RT- and DNA-PCR for the virus and its expressed genes). This study will for the first time provide experimental insight into how the interaction of EBV and P. falciparum malaria increases the risk for eBL. It will also have the direct clinical implication that intervention to reduce the malarial burden and the ability of malarial antigens to trigger AID could dramatically reduce the incidence of an important childhood lymphoma - eBL.
Endemic Burkitt's lymphoma is the most common cancer in African children. This proposal presents the first coherent explanation for the association of this tumor with Epstein-Barr virus and P. falciparum malaria infection and will provide a rationale for development of therapeutic and prophylactic intervention against the tumor.
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