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Title: Regulation of TGFβ and BMP signalling in human B cells by latent Epstein-Barr virus
Author: Eccersley, Lydia
ISNI:       0000 0004 5918 3761
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Most individuals are infected with EBV, which establishes latent infection in B cells. Although usually asymptomatic, EBV persistence is associated with several types of lymphoma. TGFβ signals via TGFβ receptors (TGFβR) 1 and 2 and is generally pro-apoptotic and anti-proliferative, but EBV infection renders cells resistant to these effects. The aim of this thesis was to investigate further the mechanism by which this occurs. Using the EBV-negative Burkitt lymphoma cell line BL31 infected with a panel of BAC-derived wild-type and recombinant EBVs, this study has confirmed by qRT-PCR that EBV down-regulates TGFβR2 transcription, leading to suppression of TGFβ signalling as detected by western blot for phosphorylated SMAD2. Use of recombinant viruses with deletions of individual latent proteins has shown that LMP1, LMP2A, EBNA3B and EBNA3C cooperate in this repression of TGFβR2 and suppression of signalling. Chromatin immunoprecipitation analysis has shown that the repression of TGFβR2 is accompanied by deposition of the repressive epigenetic mark histone H3 lysine 27 trimethylation and concomitant binding of SUZ12, a subunit of polycomb-repressive complex 2, to the TGFβR2 promoter. Infection of primary B cells with EBV also leads to repression of TGFβR2 and suppression of TGFβ signalling. Additionally, EBV up-regulates TGFβR3, a co-receptor for signalling by both TGFβ and bone morphogenetic proteins (BMPs), a related group of ligands which signal via SMADs 1, 5 and 8. This led to an investigation into the effects of EBV on BMP signalling. Although EBV increases signalling in response to BMP2, BMP4 and BMP6 in BL31 cells, this is not via the up-regulation of TGFβR3. BMP2 and BMP4 induce G1 arrest in BL31 cells, but EBV does not alter this. EBV also up-regulates SMAD1 and down-regulates SMAD5. The polycomb-mediated repression of TGFβR2 is a mechanism by which EBV might promote lymphomagenesis. In addition, the finding that EBV alters several components of BMP signalling suggests that BMP signalling may be important in B-cell biology.
Supervisor: Allday, Martin Sponsor: Leukaemia & Lymphoma Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available