Nadal
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Infektiologie, Abteilung » Prof. Dr. David Nadal » Nadal
Current research project
| Title / Titel | Establishment of a tractable mouse model to study γ-herpesvirus-induced lymphomagenesis |
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| Abstract (PDF, 14 KB) | |||
| Summary / Zusammenfassung | A variety of cancers have been linked to Epstein-Barr virus (EBV) that is found in >90% of the adult human population. Following primary infection, which occurs mainly during childhood, latent EBV persists in the host’s memory B-cell pool for a life-time. Occasionally, EBV may switch to lytic replication, leading to virus particle production and death of the host cell. The ability of latent EBV to transform and immortalize B-cells in vitro makes this human γ-herpesvirus a candidate for causing lymphoma. Substantial epidemiology evidence links EBV-associated Burkitt’s lymphoma to malaria, a strong stimulator of innate immunity, especially via Toll-like receptor (TLR)9 and TLR4. We have demonstrated that TLR9 stimulation suppresses lytic EBV in de novo infection and reactivation from latent infection. This suppression may affect the transformation potential of EBV as more B-cells would be predicted to carry latent EBV. Due to the inability to investigate the involvement of TLR stimulation in EBV-induced lymphoproliferation in humans, an alternate model is required. In work in progress, we have shown that TLR9 stimulation similarly suppresses lytic murine γ-herpesvirus (MHV)-68, the accepted pathogen to model in vivo γ-herpesvirus infection. Despite the growing information about the components of the immune system involved in the regulation of γ-herpesviruses infection and latency gained from experiments with MHV-68 little is known how these factors influence γ-herpesvirus-associated tumorigenesis. Here, we propose to establish a tractable mouse model to study γ-herpesvirus-associated malignancies. Like EBV in man, lymphoma induction by MHV-68 is very inefficient in the majority of immunocompetent mice. Our hypothesis is that stimulation of innate immunity will increase γ-herpesvirus-associated lymphomagenesis. Therefore, we will test different systems based on distinct murine genetic backgrounds and stimulants of innate immunity as well as the proinflammatory agent pristane that induces c-myc deregulation, the hallmark of Burkitt’s lymphoma, to model different types of γ-herpesvirus-associated malignancies. The murine genetic backgrounds will include ß2 microglobuline-/- mice which lack CD8+ T-cells, CD4-/- mice which lack CD4+ T-cells, and Rag2-/-γC-/- mice which completely lack T- and B-cells and can be reconstituted with bone marrow cells derived from mice with either wild-type or modified genetic background. The effect of innate immune stimulation on MHV-68-driven lymphomagenesis and how this affects viral replication and onset of viral-associated B-cell lymphoproliferation will be tested by using TLR9 and TLR4 stimulation as surrogate model for innate immune activation. We choose TLR9 and TLR4 stimulation due to the high level expression of these TLRs on B-cells where MHV-68, like EBV, maintains latency. In parallel with the experiments assessing cancer growth, we will also characterize the cytokine responses of the mice during prolonged innate immune stimulus as interleukin (IL)-6 and IL-10 are known to promote lymphoproliferation. We expect higher cytokine levels in mice treated with TLR9 or TLR 4 stimulants and in mice showing increased MHV-68-induced lymphoproliferation. Finally, we will determine the amount of cells with latent MHV-68 following the chronic immune activation. We predict to find more MHV-68 genome-positive cells in the spleens of animals treated with TLR stimulants. |
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| Keywords / Suchbegriffe | gamma-herpesvirus, lymphoma, 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 | Jan 2009 to Dec 2012 |