Central roles of mycobacterial type VII secretion systems in intra- and inter-kingdom warfare

Bacteria interact with their environment via specialised secretion systems that deliver proteins outside of the cell. Due to a bias in research efforts, for many years such systems were assumed to be unique to Gram-negative bacteria. A major exception is the type VII secretion system (T7SS), which is widespread in Gram-positive bacteria and actinobacteria, including the important human pathogen Mycobacterium tuberculosis. The T7SS is a complex secretion apparatus that exports folded proteins and even protein complexes. While secreted substrates are well-known for being crucial players in host-pathogen interactions, our recent data indicate that specific substrates of the relevant opportunistic pathogen Mycobacterium abscessus and the fish pathogen Mycobacterium marinum are also involved in interbacterial antagonism. This makes T7SSs important factors to understand microbial interactions, also for the understudied part of the microbial world. While the mechanism of secretion via T7SSs remains little understood, our preliminary data show that not only their roles but also their substrates are more diverse than thus far thought. Here, we unite leading experts in microbiology, structural biology, cell biology, and biophysics to spearhead research on mycobacterial T7SSs and their roles in both interbacterial and host-pathogen interactions. In this unique consortium, we will (i) define the full trans-envelope T7SS by atomic force microscopy and cryo-electron microscopy, (ii) study the mechanism of transport by creating translocation intermediates, (iii) expand the set of T7SS substrates by extensive proteomics and bioinformatics analysis, and (iv) visualise the role of T7SS in bacterial warfare and host-pathogen interactions using microfluidics, innovative lung-on-a-chip infection models and time-lapse microscopy. This will deliver a deep mechanistic understanding of the diverse roles of mycobacterial T7SSs and provide clues to exploit these systems to combat infections.