EBV Infection, Malaria & Burkitt's Lymphoma

Thorley-Lawson & Torgbor Spotlight

David and Charles and their model of endemic Burkitt's lymphoma pathogenesis

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In the Thorley-Lawson laboratory, we study persistent infection by Epstein-Barr virus (EBV), and the wide range of cancers with which it is associated. These issues are a major focus of the research conducted by Immunology PhD student Charles Torgbor.

EBV is a γ-herpes virus which establishes and maintains a benign, lifelong persistent infection in the Waldeyer’s ring (tonsils and adenoids) of >90% of the world’s population. The virus is transmitted through saliva contact and primary infection of children is asymptomatic but if it infects teenagers or adults, acute mononucleosis may occur, this is nicknamed the “kissing disease”. Our laboratory has previously investigated the mechanism by which EBV establishes and maintains a persistent infection in vivo ultimately producing the germinal center model (GCM) of EBV persistence. According to the GCM, EBV exploits the normal B cell differentiation route to establish and maintain persistent infection in a quiescent state in resting memory B cells for the lifetime of the host. EBV uses a unique transcription program at each stage of this process. The GCM has also revealed potential precursors for cancers like Burkitt’s (BL) and Hodgkin’s lymphomas.

Previously, we solved a 50 year old mystery as to why infection by Plasmodium falciparum malaria is associated with the EBV positive lymphoma endemic BL (see Figure). We showed that chronic malaria infection activates the DNA mutating/cutting enzyme, activation induced cytidine deaminase (AID), as well as the oncogene c-Myc. Upregulated/deregulated AID is a high risk for BL development because it is known to cause the hallmark c-myc/IgH translocation that drives BL. We further showed that it is hemozoin, a byproduct of red blood cell digestion by the malaria parasite, which is responsible in part for maximal AID induction. We also found that chronic malaria infection dramatically increases the number of cells latently infected with EBV that transit the germinal center (GC) where BL originates. Thus P. falciparum malaria increases the number of GC cells able to tolerate a c-myc translocation i.e. EBV infected (1 in the figure) whilst also increasing the probability that a deregulated c-myc will actually occur in these cells (2 in the figure) therefore increasing the chances that BL will arise.

Currently, our focus is to elucidate how EBV causes lymphoma in immunosuppressed (HIV infected and organ transplant patients), as well as elderly people. When EBV infects B cells in vitro it employs a unique transcription program called the growth program or latency III to drive their proliferation - a property that explains the link of EBV to cancer. This results in immortalized lymphoblastoid cell lines (LCLs). It is this gene profile that is expressed in the lymphomas. We have identified a novel reservoir of EBV infected cells in the Waldeyer’s ring. As opposed to resting memory B cells, where the virus is quiescent, these newly found cells resemble LCLs and thus have the correct characteristics to be the precursors that seed cancer in these patients. After fully characterizing these cells, we can propound monitoring and preventive strategies as well as therapies for cancers that arise from them.

Torgbor C, Awuah P, Deitsch K, Kalantari P, Duca KA, Thorley-Lawson DA. 2014. A multifactorial role for P. falciparum malaria in endemic Burkitt's lymphoma pathogenesis. PLoS Pathog. 10: e1004170. books

Roughan JE, Torgbor C, Thorley-Lawson DA. 2010. Germinal center B cells latently infected with Epstein-Barr virus proliferate extensively but do not increase in number. J Virol. 84: 1158-1168. books

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