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Modulation of innate immune responses in nasopharyngeal epithelial cells by the Epstein-Barr virus (EBV)-encoded latent membrane proteins LMP2A and LMP2B

Murphy, Stephen Fintan (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

The Epstein-Barr virus (EBV)-encoded Latent membrane proteins (LMP) 2A and LMP2B are frequently expressed in a number of EBV-associated malignancies. Although the true function of these proteins remains to be elucidated, LMP2A appears to function as a surrogate B-cell receptor in B-cells, preventing BCR signalling and ensuring viral latency. Much less is known about the function of these proteins in epithelial cells, although LMP2A has been shown to modulate Wnt/\(\beta\)-catenin, MAPK and PI3K/Akt signalling, whilst LMP2A and LMP2B have been shown to promote cell motility and to alter the turnover of certain classes of immune receptors. Viral infection of the host cell triggers the innate immune system to promote and sustain the initiation of an anti-viral state. Viruses have developed immune evasion strategies to counteract the effects of this immune response and to prevent recognition of viral antigens by the adaptive immune response. Here novel functions for LMP2A and LMP2B are described with respect to modulation of innate immunity, findings which have implications for the role of these proteins in EBV-driven oncogenesis. The first wave of the innate immune response is mediated by Toll-like receptors (TLRs), a family of PAMP receptors that transduce signals to activate the type I interferon response. Findings presented here show that LMP2A attenuates signalling from a number of these receptors in response to TLR agonist stimulation. These data were observed only in LMP2A expressing cells while those expressing LMP2B showed no alteration of TLR signalling, indicating that the amino-terminal signalling domain of LMP2A controls these functions. Preliminary findings have also identified a role for LMP2A and LMP2B in the control of vesicular trafficking, with both proteins increasing endosomal-lysosomal trafficking and lysosomal acidification, an effect that important for degradation and turnover of receptors. These data present novel mechanisms by which EBV may evade immune responses and in doing so, contribute to the progression of the EBV-associated epithelial cell malignancy, NPC.

Type of Work:Ph.D. thesis.
Supervisor(s):Young, Lawrence
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Studies
Subjects:QR355 Virology
QR180 Immunology
Institution:University of Birmingham
ID Code:1033
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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