IMIB - Institute for Molecular Infection Biology

Unraveling the Type VII secretion system (T7S) of Mycobacterium tuberculosis

Mycobacteria, members of the new order of Corynebacteriales, are gram-positive bacteria responsible for human diseases such as tuberculosis and leprosy. They   possess a highly complex cell wall, made of inner lipid bilayers, glycans and the mycomembrane. The mycomembrane distinguishes Mycobacteria from other   Gram-positive bacteria and shields them against extreme extracellular conditions. At the same time these hydrophobic layers pose a great challenge for delivering   virulence factors to the host.      

To overcome this problem, mycobacteria have evolved specialized translocation machineries that traverse the complex cell-wall and mediate secretion of these antigenic targets (Esx proteins). In five different genetic loci, the coding sequences for Esx proteins are flanked by conserved genes coding for components of the translocation machinery and accessory proteins.

These 5 paralogous gene clusters, named ESX-1 to ESX-5, have been linked to host-pathogen interactions and pathogenicity of M. tuberculosis. Preliminary studies indicate that T7S systems are tightly regulated and employed at different stages of the infection to release specific sets of substrates.

We propose to employ a variety of different biophysical and biochemical tools in order to gain insight into the assembly and function of the translocon. Our primary interest lies on the structural elucidation of the individual core machineries of ESX/TypeVII secretion system (M. tuberculosis H37Rv). At the same time we aim to characterize protein-protein interactions among the secretory substrates and other proteins of the system (e.g. ATPases that are essential for successful protein secretion). The combination of a structural and biochemical approach should expand our understanding of substrate recognition and translocation mechanism.