Research Report 2010 2011 - Helmholtz-Zentrum fÃ¼r ...

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114 SCIENTIFIC REPORTS | Infection and Immunity | New Project Groups New Project Groups The HZI has given young researchers with very good ideas the possibilities to do their research at the HZI facilities when their scope has been within the forthcoming R&D developments of the Centre. Since 2009 further new projects groups have started their work at the HZI. During the next 5 years they will try to establish new research ways and present excellent results. The fi r s t results and further ideas of this 2 nd generation of new R&D groups are presented on the next pages. The platform in the Gründerzentrum of the HZI, where new project groups have the possibilty of presenting their research results. The photo was taken during a visit of Nobel Laureate Prof. Dr. Kurt Wütherich (La Jolla, USA / Zürich, Switzerland) (left side at the first poster) in <strong>2010</strong>. Photo: HZI
SCIENTIFIC REPORTS | Infection and Immunity | New Project Groups 115 01 Regulation and Herpesviral Immune Modulation of Toll-like Receptor Signalling PROJECT LEADER | Dr. Melanie M. Brinkmann | Junior <strong>Research</strong> Group Viral Immune Modulation | mbr10@helmholtz-hzi.de PROJECT MEMBERS | Dr. Bettina Gruhne | Elisa Reimer Herpesviruses Herpesviruses establish lifelong persisting infections. Whereas immunocompetent individuals are able to control herpesviral infections immunocompromised persons such as transplant recipients or AIDS patients can encounter severe medical problems. An infection with the betaherpesvirus cytomegalovirus (CMV) during pregnancy is the most prevalent cause for virus-induced abnormalities of the fetus. Further, the human gammaherpesviruses Epstein- Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) can cause tumours. In order to develop improved prophylactic and strategic therapies it is crucial to improve our understanding how herpesviruses are recognized by the host’s immune system and how herpesviruses modulate the immune response to avoid their detection and elimination. Innate Immune System The innate immune system allows an early and potent antiviral response and plays an important role for the induction of the adaptive immune response. One group of pathogen sensors of the innate immune system are members of the family of Toll-like receptors (TLRs). TLR9 senses herpesviral DNA and induces a potent antiviral interferon response. The cellular UNC93B protein is essential for proper functioning of TLR9: it delivers TLR9 from the endoplasmic reticulum, where it is synthesized and stored until needed, to a specialized intracellular compartment called the endosome. There TLR9 meets the DNA of the invading pathogen and initiates a signalling cascade that results in the activation of an antiviral response. Whereas the downstream signalling cascade of TLRs is well characterized little The membrane protein UNC93B interacts with Toll-like receptor 9 (TLR9) in the endoplasmic reticulum and delivers it to the endolysosomal compartment where TLR9 meets DNA of invading pathogens. Upon arrival in the endolysosome, TLR9 undergoes proteolytic cleavage which is the prerequisite for signalling and the induction of an antiviral response. Copyright Melanie M. Brinkmann TLR9 localizes to the endolysosomal compartment after TLR agonist stimulation. Primary bone marrow derived macrophages were isolated from TLR9-GFP transgenic mice. Live cells were stimulated with LPS and analysed with a spinning disc confocal microscope in real-time. Endolysosomes were visualised with lysotracker (in red). Copyright Melanie M. Brinkmann is known about the regulation of intracellular trafficking in infected antigen presenting cells. The Project Our research focuses on the mechanisms herpesviruses evolved to modulate their recognition by the host’s immune system, thereby allowing them to establish chronic infections. We have evidence that herpesviruses can modulate the antiviral response initiated by TLRs. We aim to identify the responsible herpesviral genes and characterize their mechanism of action. We further study the regulation of intracellular trafficking of TLR9 upon infection with herpesviruses. Using fluorescently labelled virions and fluorescently labelled TLR9 and UNC93B proteins, the group will analyse intracellular trafficking in real-time in primary antigen presenting cells by confocal lasermicroscopy. In a biochemical approach, using herpesviral DNA as bait, we aim to identify further DNA sensors that are crucial for the detection of herpesviruses. Furthermore, we identified novel interacting partners of the UNC93B protein and will characterize their role for trafficking of the UNC93B-TLR9 complex from the endoplasmic reticulum to the endolysosomal compartment where TLR9 signalling is initiated. Boyoun Park, Melanie M. Brinkmann, Eric Spooner, Clarissa C. Lee, You-Me Kim and Hidde L. Ploegh, (2008) Nature Immunology, 9 (12), 1407-1414 You-Me Kim, Melanie M. Brinkmann, Marie-Eve Paquet and Hidde L. Ploegh (2008) Nature, 452 (7184), 234-238 Melanie M. Brinkmann, Eric Spooner, Kasper Hoebe, Bruce Beutler, Hidde L. Ploegh and You-Me Kim, (2007) Journal of Cell Biology, 177 (2), 265-275
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SCIENTIFIC REPORTS 91 Infection and
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PORTRAIT 5 The task of the chemists
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FOREWORD | Prof. Dr. Dirk Heinz 7 F
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OBITUARY | Jürgen Wehland 9 Jürge
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SCIENTIFIC REPORTS FACTS AND FIGURE
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FACTS AND FIGURES 177 Members of th
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180 IMPRINT Research Report 2010/11
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ISSN 1865-9713 Helmholtz-Zentrum f
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