Mycobacterium tuberculosis is the single, deadliest bacterial pathogen worldwide as the etiological agent of tuberculosis (TB). In 2022 alone, over 10 million new cases appeared, and 1.6 million people died from TB, while approximately one quarter of the world’s population was estimated to carry the disease asymptomatically. However, tuberculosis is not the only mycobacterial disease, with a suite of other mycobacterial pathogens causing diseases such as leprosy, Buruli ulcer and others.
Despite the world scale commitment, via the End TB strategy, TB remains a global threat. As outlined in the strategy, the TB global incidence should have already decreased at a rate more than twice, while the funds necessary for care, prevention and R&D face a gap of approximately 3 billion euros. To make matters worse, the Covid-19 pandemic has reversed the last ~5 to 7 years of progress in the fight against the disease.
Type VII secretion systems (T7SSs) are specialized secretion systems used by mycobacteria to export proteins and virulence factors across their very specific and impermeable, diderm cell envelope. They play central roles in mycobacteria, ranging from virulence to uptake of iron or nutrients to conjugation of DNA. The aim of this project was to uncover the structural basis of T7SS protein transport across the mycobacterial cell envelope, focusing on elucidating the fully assembled T7SS inner-membrane translocation machinery and identifying the components responsible for protein translocation across the mycobacterial outer-membrane.
