Epstein-Barr virus; Memory B-cell; Persistence; Latency; Integrins; Signaling
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Azzi Tarik, Lünemann Anna, Murer Anita, Ueda Seigo, Béziat Vivien, Malmberg Karl-Johan, Staubli Georg, Gysin Claudine, Berger Christoph, Münz Christian, Chijioke Obinna, Nadal David, Role for early-differentiated natural killer cells in infectious mononucleosis., in Blood
The medical importance of the Epstein-Barr virus (EBV), a member of the ?-herpesvirus family, relates to its association with cancer including B cell tumors. EBV infects more than 90% of the adult population and persists in memory B cells in a latent form. Latent EBV exhibits a unique capacity to transform B cells in vitro giving rise to lymphoblastoid cell lines (LCLs). How EBV gains access to memory B cells is a matter of debate. We showed that EBV infects and transforms more efficiently memory B cells from nasopharyngeal-associated lymphoid tissue (NALT) including tonsils, the portal of entry and exit of EBV, than from peripheral blood. Also, we found that memory B cells from NALT express higher levels of ß1 integrin, blocking of ß1 integrin inhibits infection of NALT memory B cells by EBV, and triggering CD40 and the B-cell receptor augments ß1 integrin expression in peripheral blood memory B cells plus their susceptibility to infection by EBV.We hypothesize that EBV exploits the B cell differentiation status and tissue of origin to establish persistent infection. We propose to test this hypothesis by i) establishing the role of integrins in EBV infection of memory B cells and the mechanisms involved; ii) modeling the susceptibility to EBV infection of memory B cells of known antigen specificity from NALT vs. non-NALT; iii) EBV infecting non-NALT memory B cells of known antigen specificity following stimulation similar to that occurring in NALT; and iv) investigating the latent and lytic behavior of EBV in acutely or chronically EBV-infected memory B cells of known antigen specificity upon polyclonal or cognate antigen stimulation to model effects operative on EBV-infected memory B cells in NALT. To this end, we will use tools that are well established in our laboratory including cell culture, flow cytometry, cell sorting, and molecular biology methods. In addition, we will elaborate specific enzyme-linked immunospot (ELISPOT) assays to detect memory B cells of known antigen specificity. To model memory B cells generated in NALT versus non-NALT we will investigate memory B cells from patients with influenza or measles versus from vaccinees recently immunized against influenza, measles, or tetanus toxoid. This project will elucidate the quantitative a and ß integrin expression in naïve and memory B cells from tonsils and other lymphoid tissues and their contribution in enhancing susceptibility of memory B cells to EBV infection. Thus, it will give a long sought-after explanation for the EBV persistence in memory B cells, given that memory B cells from NALT reside in NALT and, following circulation in the peripheral blood, are likely to home to NALT, from where EBV can infect new hosts. Also, the understanding of the mechanisms governing the balance of latent and lytic EBV in memory B cells will be improved. This is key for gaining critical insights into the pathogenesis of EBV-associated lymphomas and for the engineering of cancer cell-tailored treatment by inducing lytic EBV, thereby restricting cell death to EBV-harboring malignant cells.