In this project, the researchers, including main applicant and microbiologist Edith Houben (A-Life, Molecular Microbiology section), work together with leading experts in the fields of microbiology, structural biology, cell biology and biophysics from the Center for Structural Systems Biology (CSSB) in Hamburg, Newcastle University, and the École Polytechnique Fédérale de Lausanne (EPFL).
The scientists are studying a series of ingenious molecular machines, the type VII secretion systems (T7SSs), which occur in a special group of bacteria, the mycobacteria. These bacteria use these secretion systems to kill not only us, but also other bacteria. These weapons are essential for the world’s deadliest bacterial pathogen, Mycobacterium tuberculosis, to cause illness. But while the T7SSs are very important, little is known about how these machines work. The scientists will therefore visualise these ‘molecular weapons’ in intact bacteria, and study in detail how these systems kill both host cells and competing bacteria.
Impermeable cell wall
‘Mycobacteria have a very impermeable cell wall, which makes transport in and out of the cell, but also the treatment of these bacteria with antibiotics, very difficult’, says Houben. ‘By visualising T7SSs in intact bacteria, we will understand how these molecular machines can transport proteins through this impenetrable cell wall.’
The teams, in close collaboration with the Amsterdam UMC, have already made important contributions to the understanding of these secretion systems. First, they solved the high-resolution structure of such a system in the TB bacterium in isolated form. Second, they discovered that these systems are not only involved in manipulating and evading our immune system, but also in killing other bacteria by secreting toxins. In this project, they will use state-of-the-art electron and atomic force microscopy to visualise these molecular machines in cells. They will study in detail how these systems kill both host cells and competing bacteria using advanced microtissue models that mimic the lung environment.
This will allow the scientists to answer several important questions about the physiology and virulence mechanisms of various relevant mycobacterial pathogens. ‘This project will not only increase our understanding of T7SS, but also reveal ways to exploit these protein transport systems for new treatments of mycobacterial infections,’ says Houben. ‘I look forward to working together on this project in the coming years.’
ERC Synergy Grant
The Synergy Grants are the largest grants awarded by the ERC. They are intended to support groundbreaking research by a small group of two to four principal investigators. Together, they tackle ambitious research questions that cannot be addressed by the principal investigators and their teams alone. Synergy projects enable substantial advances at the frontiers of knowledge, for example through the cross-fertilization of scientific fields, new productive lines of research, or new methods and techniques, such as unconventional approaches and research at the interface of established disciplines.