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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018757-32
Application #
8611890
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Beisel, Christopher E
Project Start
1981-09-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
32
Fiscal Year
2014
Total Cost
$371,250
Indirect Cost
$146,250
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Thorley-Lawson, David; Deitsch, Kirk W; Duca, Karen A et al. (2016) The Link between Plasmodium falciparum Malaria and Endemic Burkitt's Lymphoma-New Insight into a 50-Year-Old Enigma. PLoS Pathog 12:e1005331
Thorley-Lawson, David A (2015) EBV Persistence--Introducing the Virus. Curr Top Microbiol Immunol 390:151-209
Qiu, Jin; Smith, Pamela; Leahy, Leah et al. (2015) The Epstein-Barr virus encoded BART miRNAs potentiate tumor growth in vivo. PLoS Pathog 11:e1004561
Torgbor, Charles; Awuah, Peter; Deitsch, Kirk et al. (2014) A multifactorial role for P. falciparum malaria in endemic Burkitt's lymphoma pathogenesis. PLoS Pathog 10:e1004170
Qiu, Jin; Thorley-Lawson, David A (2014) EBV microRNA BART 18-5p targets MAP3K2 to facilitate persistence in vivo by inhibiting viral replication in B cells. Proc Natl Acad Sci U S A 111:11157-62
Hawkins, Jared B; Delgado-Eckert, Edgar; Thorley-Lawson, David A et al. (2013) The cycle of EBV infection explains persistence, the sizes of the infected cell populations and which come under CTL regulation. PLoS Pathog 9:e1003685
Thorley-Lawson, David A; Hawkins, Jared B; Tracy, Sean I et al. (2013) The pathogenesis of Epstein-Barr virus persistent infection. Curr Opin Virol 3:227-32
Tracy, Sean I; Kakalacheva, Kristina; Lunemann, Jan D et al. (2012) Persistence of Epstein-Barr virus in self-reactive memory B cells. J Virol 86:12330-40
Smith, Pamela A; Merritt, David; Barr, Leah et al. (2011) An orthotopic model of metastatic nasopharyngeal carcinoma and its application in elucidating a therapeutic target that inhibits metastasis. Genes Cancer 2:1023-33
Hawkins, Jared B; Jones, Mark T; Plassmann, Paul E et al. (2011) Chemotaxis in densely populated tissue determines germinal center anatomy and cell motility: a new paradigm for the development of complex tissues. PLoS One 6:e27650

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