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Georg Häcker (2011-2017)

Establishment and maintenance of the chlamydial inclusion: requirement for septins and the inhibition of host cell translation

The obligate intracellular bacterium Chlamydia trachomatis develops and grows in a vacuole termed inclusion. The inclusion is formed in isolation from endocytic pathways but is in contact with post-Golgi-traffic. At the conclusion of bacterial development, the inclusion is often released intact by exocytosis/extrusion. C. trachomatis can secrete bacterial proteins into the cytosol that are believed to orchestrate the incorporation of the inclusion into the cell and to secure nutrient supply to the bacteria; the most prominent is the protease CPAF. In our preliminary work we have made two observations that form the basis of this proposal: first, we observed that 4 septins, proteins that can form cytoskeletal structures and probably transport structures, arrange F-actin on the inclusion and co-determine bacterial release as well as post-Golgi nutrient supply to the inclusion. Secondly, infection causes a markedly enhanced degradation and a reduced synthesis of host cell proteins. The first aim of this project is to understand the role of septins in anchoring of the inclusion and nutrient supply of the bacteria. Through analysis of cytoskeletal embedding of the inclusion, through high-resolution imaging of structures and transport processes and through monitoring of bacterial development we will endeavour to understand how septins are involved in the growth of inclusion and bacteria. The second part aims at understanding extent and mechanism of enhanced degradation and altered protein synthesis and their effects on the development of the inclusion. We believe that Chlamydia specifically targets protein levels through enhanced proteolysis to alter cell biological programmes in its favour (such as organelle arrangement, vesicular transport, apoptosis). Using global and specific analysis we will investigate how C. trachomatis (possibly through CPAF) affects host cell protein levels and how these manipulations contribute to establishment and maintenance of the inclusion.



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