Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells

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The successful infection strategy of pathogenic bacteria often relies on the translocation of bacterial effector proteins into infected host cells that target dedicated host cellular functions to the benefit of the pathogen. Bartonella spp. are facultative intracellular pathogens that infect a wide range of mammalian hosts including humans. In order to escape the immune response of their hosts these “stealth” pathogens utilize a type IV secretion system to translocate a cocktail of Bartonella effector proteins (Beps) into infected host cells. Crucial for Bep secretion into host cells is the Bep intracellular delivery (BID) domain, that has been further shown in specific cases to modulate diverse host cellular processes. Thus, the BID domain is the first known example of a protein secretion signal domain that has adopted additional effector functions. However, the respective structural requirements of the BID domain for Bep-translocation and effector function are not understood. The objective of this research project is to elucidate the dual role of the BID domain in 1) effector translocation and 2) modulation of host cellular processes. This project will focus on the structural and functional elucidation of BID-target interactions involved in Bep-translocation into host cells and modulation of host cellular processes. In order to understand these processes, a combination of bacterial genetics, protein translocation and physiological assays, biophysical methods and structural analyses will be used. The fellowship will include training of the experienced researcher in advanced techniques that will lead to his scientific independency. Results of this project will be important for the fields of molecular microbiology and infection biology and will contribute to a better molecular understanding of bacterial effector translocation and function.