Nadal
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Infektiologie, Abteilung » Prof. Dr. David Nadal » Nadal
Current research project
| Title / Titel | Is endemic Burkitt's lymphoma really promoted by chronic innate immunity triggering by malaria infection? | ||||
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| Abstract (PDF, 14 KB) | |||||
| Original title / Originaltitel | Begünstigt chronische Stimulation der angeborenen Immunität durch Malaria die Entstehung des Burkitt Lymphoms? | ||||
| Summary / Zusammenfassung | Epstein-Barr virus (EBV) is a B-lymphotropic gamma-herpes virus which infects >90% of the human population and establishes latent infection in the host’s memory B-cell pool. The virus was first detected in endemic Burkitt's lymphoma (BL) and subsequently in other cancers including lymphomas of B, T and natural killer (NK) cell origin such as the immunoblastic lymphoma of immunosuppressed, and certain sporadic BL, Hodgkin's lymphoma, and nasal T/NK lymphoma. The oncogenic potential of EBV is illustrated by its ability to transform B-cells in vitro whilst in its latent state. In areas where malaria is holoendemic, latent EBV is particularly strongly associated with the development of endemic BL. However, the malaria parasites’ contribution to the establishment and survival of endemic BL is not fully understood. It probably involves multiple immunomodulatory effects and B-cell activation. Most noteworthy, malaria DNA, conjugated to the malaria pigment hemozoin, is a ligand and trigger for Toll-like receptor-9 (TLR9), a key component of the innate immune system, eventually resulting in activation of the transcription factor NF-kappaB. This finding becomes significant considering that in vitro B-cell transformation induced by EBV is efficiently increased in the presence of TLR9 ligands. We have shown that immune activation specifically via the TLR9 ligand ODN CpG2006 suppresses EBV lytic gene expression in ex vivo EBV-infected B-cells and in the chronically EBV-infected BL cell line Akata. We have started the characterization of the molecular mechanisms involved and have documented that NF-kappaB is most likely not involved in repression of EBV lytic gene expression upon TLR9 triggering in Akata cells. We hypothesize that chronic activation of TLR9 favors the insurgence of EBV-associated endemic BL by interfering with cellular and viral components. We will test this hypothesis by examining the interference of TLR9 signaling on cellular and viral components at three sequential key pathogenic events in lymphomagenesis: First, influence of chronic TLR9 triggering on establishment and maintenance of latent EBV; second, effect of chronic TLR9 triggering on efficiency of EBV-driven B-cell transformation; and third, impact of chronic TLR9 triggering on proliferation of EBV-transformed B-cells. Thus, we will confirm that NF-kappaB is not responsible for the TLR9-induced suppression of lytic EBV gene expression using Akata BL cells transfected with I-kappaB, a more physiological and specific inhibition compared to that of chemical inhibitors of NF-kappaB. Next, we will investigate the role of the adaptor protein MyD88 in TLR9-induced suppression of EBV lytic gene expression using Akata cells transfected with a dominant negative MyD88 mutant and the inhibitory peptide ST2825, respectively. To identify the EBV gene elements involved in repression of EBV lytic gene expression we will establish reporter systems in BL Akata cells. These systems will allow us to determine the specific EBV genomic region mediating TLR9 negative regulation of EBV’s master lytic gene BZLF1. Further, we will test the replication and transformation effect of TLR9 triggering in B-cells from patients with EBV-positive lymphomas as compared to matched controls. Finally, we will investigate the effects of chronic TLR9 triggering on proliferation of BL cells Akata and Mutu expressing EBV LMP2A which keeps the virus in its latent state. |
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| Keywords / Suchbegriffe | Burkitt's lymphoma, Epstein-Barr virus, malaria, innate immunity | ||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Foundation |
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| Duration of Project / Projektdauer | Oct 2009 to Sep 2012 |