Epstein-Barr virus (EBV) infects and persists in >95% of the human population but is also associated with important forms of lymphoma, carcinoma and possibly autoimmune disease. We now have a detailed model of how EBV establishes persistent infection based on the concept that it uses the normal biology of B lymphocytes to gain access to and persist within the memory B cell compartment. At the heart of this model is the idea that EBV uses the germinal center (GC) reaction to convert latently infected B cells into memory cells. The GC reaction is the mechanism by which antigen activated B cells proliferate and undergo affinity maturation of their antibody molecules to become memory cells. EBV encodes proteins, LMP1 and LMP2a, that potentially have the signaling capacity to drive a latently infected cell through a GC into memory and their expression has been detected in tonsil cells bearing the GC marker CD10. However it is not known if these cells are functional GC cells or even reside within a GC. To resolve this issue we will: 1. Use flow cytometry matched with highly sensitive quantitative PCR to show that GC cells latently infected with EBV and expressing LMP1 and LMP2a, also express specific functional markers of the GC reaction. These include chemokine receptors, bcl-6, c-myc, p53 and AID. 2. Dissect whole GCs and test if they contain EBV+ B cells expressing LMP1 and LMP2a. 3. Use laser capture microdissection to isolate individual infected cells from GCs and test if they express functional GC markers. These studies will reveal whether and to what extent EBV+ cells participate in the GC reaction. This is crucial for understanding the mechanism of EBV persistence and its role in Hodgkin's disease and Burkitt's lymphoma both of which are thought to arise from GC or post GC cells. For the second goal we will analyze how EBV interacts with the host to produce latently infected memory cells. EBV has long been postulated to have a role in autoimmune diseases, including SLE and MS, because of its potential capacity to rescue autoreactive B cells. Previously this question could not be addressed, but our approach now makes this possible. We will ask if EBV+ memory B cells are antigen specific and, if so, are they autoreactive? We will use sensitive single cell RTPCR to identify the expressed immunoglobulin from EBV+ and EBV- memory cells isolated from the same individual. The PCR products will be cloned and expressed in bacterial or mammalian systems to produce the original immunoglobulins. These will be tested for autoreactivity by ELISA and immunofluorescence techniques on standard sources of autoantigens. This will answer the question of whether or not EBV promotes the survival of autoreactive B cells in vivo.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Virology - B Study Section (VIRB)
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Beisel, Christopher E
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Tufts University
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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
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
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