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Projekt
The biological role of interferon y induced 65 kDa GBPs as effector molecules in host defense
Antragsteller
Professor Dr. Klaus Pfeffer
Fachliche Zuordnung
Immunologie
Förderung
Förderung von 2007 bis 2015
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 21644054
Interferon γ (IFNγ) is a proinflammatory cytokine which plays a crucial role in the containment and clearance of infections. The IFNγ activated expression of numerous genes enables responsive cells to establish potent antimicrobial effector systems, leading to successful pathogen elimination or inhibition of replication. Some effector molecules induced by IFNγ have been characterized so far; however, the understanding of the IFNγ mediated antimicrobial response of effector cells is still largely incomplete. In particular, the 65 kDa guanylate-binding proteins (GBPs) are abundantly induced by IFNγ, but their functions are still enigmatic. In our recent studies, we could identify 6 novel members of the mGBP family (mGBP 6, -7, -8, -9, -10, and -11). We could establish that all 11 members of the mGBP family are inducible by IFNγ and are rapidly induced in mice after infection with L. monocytogenes and T. gondii. Remarkably, several mGBPs (mGBP 1, -2, -3, -6, -7, and -9) show a subcellular redistribution and direct colocalization with the parasitophorous vacuole after active invasion of T. gondii parasites. Mutations of the nucleotide binding motifs lead to an aberrant localization of the proteins in uninfected cells and to a dramatically reduced capability to relocalize to intracellular pathogens. During the last funding period gene-deficient mice for several mGBPs (mGBP1, -2, -3, and 5) were successfully generated. These mouse lines are viable and will be employed to identify non-redundant functions of individual mGPBs. We could already demonstrate that mGBP1-/- embryonic fibroblasts show a significantly reduced capability to restrain the intracellular replication of T.gondii. Furthermore, gene targeting of mGBP 6, -7, -8, -9, and -10 is ongoing and the compound targeting of the mGBP gene clusters on chromosomes 3 and 5 are proposed here. The aim of the proposed project is the characterization of the molecular effects of the mGBP proteins on diverse pathogens and their in vivo role in the defence against bacterial, viral, and parasitic infections.
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