Epstein-Barr Virus microRNA Expression and Function in Persistent Infection and Oncogenesis.
virus (EBV) infects more than 95% of the adult world population. For most people this is
not a problem as EBV seems to be exclusively harbored quiescently in resting B
lymphocytes without manifesting any symptoms. EBV has developed elaborate and
sophisticated strategies for subverting immune surveillance by the host. In this system,
EBV is able to initiate distinct ... read morelatency programs to trick B cells into accepting the
virus. Ultimately the virus is able to persist in a latent state in memory B cells such
that it is invisible to the immune system and also harmless. But on the other hand, EBV
can be a terribly notorious pathogen. This happens because on its way to quiescent
infection it temporarily drives the growth of infected cells. The ability to make cells
grow if not tightly regulated can lead to diseases especially cancer. EBV is associated
with several cancers of lymphoid and epithelial origin. The exact mechanisms by which
EBV influences cancer development are as yet unknown. MicroRNAs (miRNAs) are small
noncoding RNAs that can post-transcriptionally regulate gene expression. The EBV genome
encodes more than 40 mature miRNAs identified to date. The function of most EBV miRNAs
remains to be explored. This thesis work aimed to elucidate the roles of EBV miRNAs in
establishing latency and tumor development from three scientific perspectives. First,
with a profiling study, I identified a unique pattern of viral miRNA expression by
normal persistently infected primary B cells in vivo and a subset of miRNAs that might
be associated with cell growth and are deregulated in tumors. Second, using optimized
mouse cancer models, I found that the EBV BART miRNAs provide a growth/survival
advantage to EBV-associated tumors in vivo therefore promoting tumor growth. Lastly, by
focusing on miRNA target identification, I demonstrated that a miRNA BART18-5p
facilitates the maintenance of latency in B cells by inhibiting viral replication by
suppressing MAP3K2. In all, these studies on expression profiles and molecular functions
of EBV miRNAs provide significant insights into the role of EBV in persistent infection
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Immunology.
Advisor: David Thorley-Lawson.
Committee: Thereza Imanishi-Kari, Ananda Roy, and Alexander Poltorak.
Keywords: Immunology, and Virology.read less