Research programme: Epstein-Barr virus pathogenesis and diversity.
Epstein-Barr virus (EBV) is a ubiquitous human pathogen, capable of transforming naive B cells into proliferating lymphocyte cell lines. However, only a small proportion of EBV-positive individuals develop EBV-associated malignancies. The aim of my research program is to ascertain what factors contribute to the initiation and maintenence of EBV-associated oncogenesis. Central to this is to ask how EBV latency (particularly expression of the nuclear antigens) modifies the host transcriptome and other cellular characteristics. Additionally we must establish how the natural diversity of EBV contributes to the biology and pathogenicity of the virus.
Genetic analysis of EBNA-LP
We (and others) have previously generated genetic mutants of the EBV nuclear antigens (EBNAs) 3A, 3B, 3C and 2. Our transcriptomic analysis of cell lines carrying these genetic variants (EBNA3 data available at www.epstein-barrvirus.org.uk) provided insights into how EBV alters host cell behaviour through the combined activities of these latency-associated genes. The remaining nuclear antigen, EBNA-LP is known to enhance the activation of some host and viral genes by EBNA2, and to disrupt the nuclear PML bodies that are though to play an antiviral role, but its importance and roles in the EBV lifecycle remain speculative. We aim to generate recombinant EBV with mutations in EBNA-LP in order to establish its role in transformation and in regulating the host transcriptome.
EBV mutation in EBV pathogenesis.
Using the EBV-BAC reverse genetic system, we have recently found that EBNA3B can play a tumour suppressor role, such that its deletion induces diffuse large B cell lymphomas in a humanised mouse model system (J Clin Invest. 2012; 122:1487-502). Sequencing identified EBNA3B mutations in human lymphomas, that we hypothesise play a role in the oncogenesis of and/or immune evasion by these lymphomas. We aim to identify and characterise mutations of EBV, and identify the host processes that these mutations disrupt.
The consequences of EBV diversity.
The transformation efficiency of the B95-8 strain of EBV has led to this single strain dominating EBV research. With the advent of next generation sequencing technologies, the diversity of EBV is only now beginning to become apparent. We are studying the consequences of this diversity using in vivo and in vitro systems, with a view to developing reverse genetic systems using virus strains that more faithfully represent wild-type EBV.
Professor Paul Kellam, Sanger Institute, EBV genome sequencing, 2011
Micah Luftig, Department of Molecular Genetics and Microbiology, Center for Virology, Duke University School of Medicine, 2010
Research Student Supervision
Ba Abdullah,M, The biology of Epstein-Barr virus diversity.
Ho,G, Regulation of immune gene loci by EBNA3 proteins of EBV
Szymula,A, A reverse genetic analysis of Epstein-Barr virus latency-associated protein EBNA-LP.