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94 SCIENTIFIC REPORTS | Infection and Immunity | Infl ammation and Immunity 03.3 Immuneffectors: Molecules, Cells and Mechanisms PROJECT LEADER | Dr. Siegfried Weiss | Research Group Molecular Immunology | siw@helmholtz-hzi.de PROJECT MEMBERS | Imke Bargen | Nicole Dietrich | Dr. Sandra Düber | Dr. Nelson Gekara | Dr. Jadwiga Jablonska | Katja Kochrübe | Dr. Sara Leschner | Dr. Stefan Lienenklaus | Dr. Bishnudeo Roy | Swati Shukla | Evgeniya Solodova | Christian Stern | Dr. Nuno Viegas | Kathrin Wolf | Natalia Zietara Our immune system consists of several lines of defense. One of the first of such lines are type I interferons (IFN) with their most important members IFN-α and IFN-β. Originally, IFNs have antiviral activity but are also induced by all kinds of other infections and play an important role under normal physiological conditions. In our experiments, we could show that in macrophages IFNs are also induced by ligands of the toll like receptor 2 (TLR2). TLR2 ligands are found in the cell wall of Gram-positive bacteria and mycoplasms. Interestingly, to be able to trigger IFN production, the TLR2-ligand complex has to be endocytosed by the macrophages. Inhibition of endocytosis leaving the receptor-ligand complex at the cell surface allows only production of pro-inflammatory cytokines like TNF-α. In accordance, the ability of a cell to endocytose surface TLRs decides whether the cell can produce IFNs after TLR-ligand binding or not. Along this line, we could show that mast cells are not able to endocytose such TLRs or to phagocytose bacteria that might have engaged TLRs. Therefore, mast cells are not able to produce IFN during an infection by bacteria although they are perfectly able to do so in case of a virus infection. Anatomically, mast cells are positioned underneath the various epithelia. Most likely, they represent the first immune cells to encounter pathogens that invade the body. During bacterial infection production of IFN is often detrimental. Thus, the lack of IFN production and the restriction of mast cells to the secretion of pro-inflammatory cytokines might represent a well-balanced evolutionary adapted defense mechanism. We noticed that mice that lacked the gene for IFN-β or of one of the receptor chains (IFNAR) exhibited an altered angiogenesis i.e. formation of blood vessels. This was especially obvious in fast growing transplantable tumours: In IFN-β koor IFNAR ko-mice the tumours grew much faster. This was due to an enhanced angiogenesis resulting in more and more mature blood vessels in tumours of the recombinant mice. We could show that neutrophilic granulocytes were involved in this process (Figure 1). Without a functional IFN system the tumours contained more of such granulocytes and they produced more pro-angiogenic factors. By isolating granulocytes from tumours of the ko-mice we could show that already small amounts of IFN-β down-regulate the production of the pro-angiogenic factors. Thus, it becomes clear that IFNs are a natural component of the tumour surveillance system of our body. Many bacteria like Salmonella typhimurium migrate to solid tumours after systemic application and proliferate there. Thus, they can be used as shuttle to express therapeutic genes directly in the neoplastic tissue sparing the healthy organs. Enhanced tumour angiogenesis and growth is mediated by neutrophilic granulocytes unresponsive to type I IFN. Mice were subcutaneously injected with B16F10 melanoma cells that were mixed either with neutrophils obtained from tumor bearing Ifnar1 -/- mice (IFNAR-/-+B16) or from tumour bearing wild type mice (C57BL/6+B16). The tumours mixed with IFN-unresponsive neutrophils grew much faster. Blood vessels in the tumors were investigated by immune histology using anti-laminin to stain endothelial cells (red) and anti-actin to stain smooth muscle cells (green). The presence of high amounts of actin in the IFNAR-/- +B16 tumours is indicative for the enhanced maturity of the blood vessels and thus of a better blood supply of the tumour. Photo: HZI Essential for the specific expression of such substances is the definition of bacterial promoters that restrict expression to the tumour. To this end we have screened a so-called promoter-trap-library with our Salmonella and could detect several promoters with the appropriate specificity. Presently, we characterize such promoters using bioinformatics as well as experimental approaches. In parallel, we investigated tumour-specific bacterial gene expression using micro expression arrays. We were able to define more than 20 genes that were specifically expressed in the tumour and not in the spleen. First of all this will help to understand the physiological status of the bacteria residing in the tumour. In addition, this will also lead to additional control elements that will enable us to express therapeutic genes specifically in the cancerous tissue.
SCIENTIFIC REPORTS | Infection and Immunity | Infl ammation and Immunity 95 03.4 Interferons in Viral Defence and Immunity PROJECT LEADER | Dr. Andrea Kröger | Department of Gene Regulation and Differentiation | akg@helmholtz-hzi.de PROJECT MEMBERS | Katja Finsterbusch | Lucas Kemper | Dr. Mario Köster | Antje Ksienzyk | Ramya Nandakumar | Berit Neumann | Dr. Ulfert Rand Interferons (IFNs) are central signalling molecules in the defense against pathogens and have essential functions in the interplay of immune cells. The IFN system is the first line of defense against infections. The effect is based on the transcriptional activation of multiple antiviral and immune modulatory genes. The aim of the project is to characterize the molecular and cellular context of host defense against infections. The detailed understanding of the involved mechanisms and the spatio- and temporal dynamics will open new opportunities for the prevention of infectious diseases. The IFN network The network of IFN production and action is strictly regulated, and its deregulation can lead to a pathologic condition in the host. Spatio-temporally resolved single cell data on viral infections have revealed IFN induction mechanisms to be a highly stochastic process while the response to IFN is bimodal. Based on these data dynamics and quantitative mathematical models describing the underlying signaling circuits are developed. This should allow the prediction of the outcome of an infection. To investigate the coordinated functions of the IFN network in vivo we generated reporter mice which allow the investigation of the IFN signal distribution in the whole body. With these tools we found that viruses with different pathogenicities lead to IFN responses which differ in quality, quantity and temporal activity. Fail-safe pathway for antiviral activity Many viruses have developed strategies to circumvent the IFN system and thereby avoid the defense of the host. We identified an alternative mechanism of antiviral defense which is IFN-independent. The transcription factor IRF-1 plays an important role in this IFN-independent mechanism. Mice which lack IRF-1 are more susceptible against viral infections. We identified viperin as a gene which plays a major role in this effect. On encountering viral infections the IRF-1 gene usually regulates the IFN response, but if the virus has developed strategies to circumvent this response there is an alternative interferon independent mechanism of antiviral defense. The impact of the IFN-independent mechanism in host defense will be investigated in other infection models like HCV. Signal progression during viral infection Time-lapse microscopy of IFN induction (green) and response (red) resolves spatio-temporal dynamics in IFN signal propagation. Photo: HZI IRF-1 induces innate and adaptive immune responses Apart from the antiviral response the IFN system is also essential for the induction and stimulation of immune responses. Enhanced immune cell activation is critical for anti-tumour responses. The expression of IRF-1 in a lung metastases model inhibits the development of metastases. This effect is mediated by the attraction and activation of natural killer cells. Concurrently, the induction of IRF-1 results in tumour specific CD8+ T cell response which protects against secondary tumour development. The inflammatory tumour microenvironment plays an important role in the outcome of the immune response. Detailed analysis of the microenvironment and the signalling cascades of the infiltrating immune cells will elucidate the mechanism of immune response induction in future. Stirnweiss, A., Ksienzyk, A., Klages, K., Rand, U., Grashoff, M., Hauser, H., Kröger, A. (2010) IFN regulatory factor-1 bypasses IFN-mediated antiviral effects through viperin gene induction. Journal of Immunology 184(9), 5179-5185. Pulverer, J.E., Rand, U., Lienenklaus, S., Kugel, D., Zietara, N., Kochs, G., Naumann, R., Weiss, S., Staeheli, P., Hauser, H., Köster, M. (2010) Temporal and spatial resolution of type I and III interferon responses in vivo. Journal of Virology 84(17), 8626-8638. Dietrich, N., Rohde, M., Geffers, R., Kröger, A., Hauser, H., Weiss, S., Gekara, N.O. (2010) Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proceedings of National Academy of the Science USA 107(19):8748-8753.
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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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180 IMPRINT Research Report 2010/11
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ISSN 1865-9713 Helmholtz-Zentrum f
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