Nadal

Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Infektiologie, Abteilung » Prof. Dr. David Nadal » Nadal

Completed research project

Title / Titel	Regulation of lytic Epstein-Barr virus infection by latent membrane protein (LMP)2A and LMP2B
PDF	Abstract (PDF, 14 KB)
Summary / Zusammenfassung	Epstein-Barr virus (EBV) is a widespread human virus which infects more than 90% of the human population. It establishes latent infection in B-cells where EBV persists throughout life. Since its discovery EBV has been associated with B-cell malignancies including Burkitt’s lymphoma (BL). During latency EBV expresses a limited number of latent genes including latent membrane protein (LMP)2A which is known to block reactivation of lytic EBV infection upon surface IgG cross-linking in EBV-transformed lymphoblastoid cell lines. By contrast, the role of LMP2B which is identical to LMP2A but is lacking the N-terminal cytoplasmic signaling domain is unknown. The C-terminal domain is able to modulate interaction in vivo, and we have recently demonstrated that genetic silencing of LMP2B decreases the induction of lytic EBV infection upon surface IgG cross-linking in BL Akata cells, as well as overexpression of LMP2A, suggesting a novel regulatory role for LMP2B. In this project we will investigate the hypotheses: i) up-regulation of the latent EBV gene LMP2A is involved in the termination of induced lytic EBV infection in BL, i.e., in terminating the up-regulation of BZLF1, and ii) the C-terminal domain of LMP2A and LMP2B is responsible for their interaction and contributes to regulation of EBV latency. Thus, we will silence expression of LMP2A in BL Akata cells, overexpress LMP2B in Akata cells, and assess the impact of these manipulations on induction of lytic EBV infection and cell metabolism. Moreover, we will generate C-terminal deletion constructs and verify the effect on induction of EBV. The exact characterization of the function of LMP2 proteins will help understanding the mechanism regulating activation of lytic EBV infection. This is of medical relevance, since induction of lytic EBV infection in EBV-harboring tumors represents a targeted approach to eliminate cancer cells while conserving normal cells. Given that the efficiency of several approaches explored for a therapeutic induction of lytic EBV infection so far is still insufficient to obtain a significant impact, the here proposed project will contribute to identify molecular targets essential to augment and optimize induction of lytic EBV infection.
Project leadership and contacts / Projektleitung und Kontakte	Prof. Dr. David Nadal, MD (Project Leader) david.nadal@kispi.uzh.ch
Funding source(s) / Unterstützt durch	Foundation Novartis
Duration of Project / Projektdauer	Jan 2007 to Dec 2007