Die Induktion von CCL3, IRF-1, IRF-7 und IL-24 durch Influenza A Virus-Infektion von Monozyten und die Bedeutung eines essentiellen Abschnittes im CCL3-Promotor

Im Verlauf einer Infektion mit dem Influenza-Virus A/PR/8 werden nicht nur respiratorische Epithelien, sondern auch Monozyten und Makrophagen infiziert. Obwohl diese für die Replikation des Virus nur eine untergeordnete Rolle spielen, sind sie für die Koordination und Verstärkung der Immunantwort de...

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Bibliographic Details
Main Author: Becker, Mike
Contributors: Gemsa, Diethard (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2008
Online Access:PDF Full Text
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The influenza A/PR/8 virus is not only infectious for respiratory epithelia, but also for monocytes and macrophages. Although these play only a minor role for the replication of the virus, they are important for the co-ordination and amplification of the immune response to the infection. The secretion of regulatory molecules, such as cytokines and chemokines, is crucial to the function of monocytes/macrophages at the interface between the innate and adaptive immune system. Primary monocytes infected by the influenza A virus secrete a variety of cytokines and chemokines, e.g. CCL3 (MIP-1α). CCL3 and its receptors CCR2 and CCR5 regulate the immune response to influenza A virus by recruiting mononuclear cells and by activating other immune cells such as T lymphocytes. Here, the transcriptional regulation of CCL3 by influenza A/PR/8 in monocytes was studied. A region within the CCL3 promotor was identified that is essential for the induction of CCL3 by infection with influenza A/PR/8 or stimulation with LPS. It could be shown that the potential transcription factor binding sites MNP and ICK within this region function synergistically, i.e. only together they are able to maximally induce transcription of CCL3 in response to the stimulus. This is true for both the influenza A infection and the stimulation with LPS. There is strong evidence that one of these binding sites, MNP, actually binds C/EBPb; the binding factors at the other site, ICK, could not be identified as yet. The induction of CCL3 after an infection with influenza A as well as after the stimulation with LPS requires binding of transcription factors at both MNP and ICK sites. This makes the factors involved likely to be part of a core response that respond to a variety of stimuli and makes them an interesting target for therapeutic intervention. The members of the interferon regulatory factor (IRF) family, too, are transcription factors activating the immune system after viral or bacterial infections These factors can be either activated by intracellular signalling pathways or can be newly induced. They in turn regulate the production of cytokines and chemokines like IL-12 and CCL5. Here, the induction of the transcription factors IRF-1 and IRF-7 after an infection of monocytes with influenza A virus was studied. An induction on the mRNA level as well as a de novo protein synthesis could be shown. This emphasises the central role of these factors in activating the immune system in response to extra- and intracellular pathogens. Interleukin-24 (IL-24) is a cytokine discovered in 1996, that has a homology to IL-10 and has been primarly studied beacuse of its anti-proliferative effect on tumour cells. Although IL-24 is different from IL-10 in its effects, it could be shown here that its mRNA is also induced in primary monocytes by an influenza A virus infection. The exact mechnisms by which IL-24 exerts its effects in the setting of viral infections are not known. However, there is evidence that IL-24 may activate the intracellular protein kinase PKR that plays an improtant role during viral infections. Further mechanisms of immune system activation by IL-24 during viral infections will have to be studied.