Epstein Barr Virus (EBV) is a gamma herpes virus that has infected >90% of the human population. EBV infection is usually asymptomatic and is controlled by a robust T cell-mediated immune response. However, EBV can also cause infectious mononucleosis and is linked to a variety of lymphoid and epithelial malignancies. Immunosuppressed transplant recipients and individuals who are immunocompromised such as AIDS patients or the elderly, are at increased risk of developing EBV+ B cell lymphomas. While impaired immunity clearly contributes to the emergence of EBV+ B cell lymphomas in these populations, the mechanisms by which EBV drives tumor cell proliferation are poorly understood. Recent studies in our laboratory indicate that EBV infection significantly alters the cellular microRNA (miRNA) profile within infected B cells. miRNA constitute an important network of small, non-coding RNA that control gene expression at the post-transcriptional level and thereby impacts cellular function. Of the miRNA that we observed are modulated by EBV, a subset is predicted to target the 3' untranslated region (UTR) of human IL-10, a known autocrine growth factor for EBV+ B cell lymphomas in transplant recipients. We have shown that one of these miRNA, miR-194, is suppressed upon EBV infection of B cells. We further show that miR-194 binds to the 3'UTR of IL- 10 and that overexpression of miR-194 in EBV+ B cell lines from transplant recipients with post-transplant lymphoproliferative disorder (PTLD) significantly inhibits IL-10 production. In this project we test the hypothesis that EBV hijacks host B cell miRNA to promote cell proliferation through constitutive production of IL-10 and that this is a novel, but targetable, mechanism of pathogenesis in EBV+ B cell lymphomas. This hypothesis will be tested in two specific aims. First, we will establish whether EBV induces human IL-10 through modulation of host cell miRNA. Second, we will determine whether targeting EBV regulation of host cell miRNA can prevent proliferation of EBV+ B cell lymphomas in vivo. The proposed studies are innovative and of potentially high impact because they will identify and define a novel mode of virally-induced pathogenesis for EBV+ B cell lymphomas and evaluate whether this constitutes a potential therapeutic target. Moreover, they will provide fundamental knowledge on regulation of IL-10 expression that could have important implications for other IL-10 producing cells.

Public Health Relevance

Epstein Barr Virus (EBV) is linked to a variety of malignancies in humans including B cell lymphoma in individuals who are immunosuppressed or immunocompromised such as transplant recipients, people with HIV, and the elderly. At the present time we do not fully understand how EBV causes cancer nor do we have effective treatment strategies. Studies in this proposal will examine whether EBV hijacks a family of molecules called microRNA, that ordinarily help to control cell function. By hijacking the microRNA network, we believe EBV causes the cells to divide without restraint; however, we anticipate that by understanding this process we can intervene and create new, more effective treatments for EBV-associated B cell lymphomas.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IMM-H (02)M)
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Beisel, Christopher E
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Stanford University
Schools of Medicine
United States
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Martinez, Olivia M; Krams, Sheri M (2017) The Immune Response to Epstein Barr Virus and Implications for Posttransplant Lymphoproliferative Disorder. Transplantation 101:2009-2016
Krams, S M; Schaffert, S; Lau, A H et al. (2017) Applying Mass Cytometry to the Analysis of Lymphoid Populations in Transplantation. Am J Transplant 17:1992-1999