A TOLL-LIKE RECEPTOR-INDUCIBLE AND B CELL-SPECIFIC ENHANCER REGULATES MURINE GAMMAHERPESVIRUS 68 LATENCY AND REACTIVATION

Murine Gammaherpesvirus 68 (MHV68) is a natural pathogen of rodents and is related to the human pathogens Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). MHV68, EBV, and KSHV are lymphotropic and are associated with a variety of lymphadenopathies, carcinomas, and lymphomas. B cells are the main latent reservoir of gammaherpesviruses. A central question is how B cell signaling regulates viral gene expression during establishment and reactivation from latency. The MHV68 M2 gene, a proposed functional analog of the EBV LMP2A and KSHV K1 genes, encodes a latency-associated protein that controls establishment and reactivation from latency. In this work, we demonstrate that the M2 gene is upregulated by stimulation of Toll-like receptor (TLR) signaling. Specifically, stimulation of TLR 2/6, 4, and 9 increased M2 gene expression in a B cell-specific manner. We show that an enhancer in the M2 intron controls M2 gene expression and inducibility by TLR signaling. This enhancer contains consensus binding sequences for transcription factors that are shared by other B cell-specific enhancers. Enhancer activity conferred by TLR stimulation was blocked by inhibitors of NF-kB or c-Jun N-terminal kinase (JNK). Overall, we determined the molecular and genetic mechanisms of M2 regulation by TLR signaling.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2014

Author dc:creator

• Barajas-Mora, Edgar Mauricio

• EBV

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/47451

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/47451