ESX-4 T7SS · Structure/function of a prototypic type VII secretion system from a fast-growing pathogenic mycobacteria
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-04-01 → 2021-03-31
- EU contribution
- €162,806
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Structure/function of a prototypic type VII secretion system from a fast-growing pathogenic mycobacteria
Mycobacteria are pathogens responsible for many infamous and widely spread diseases, like tuberculosis or leprosis. At the start of this project, no potent vaccines were available against mycobacteria and with the rise of multiple multi-drug resistant strains of mycobacteria, new drugs were needed. Though concerning, the World Health Organization (WHO) was still, with extensive efforts, optimistically hoping to eradicate TB by 2035. At the end of this study, however, the WHO stated that due to the COVID pandemic, their efforts in eradicating the century old disease were predicted to experience at least a 7-year set-back. This project aimed at studying a secretion system, specific to mycobacteria, called the Type VII Secretion system (T7SS). T7SS allows the bacteria to import important nutrients, while exporting virulent factors that lets the bacteria evade the human immune system. Therefore, this makes this study of T7SS so attractive: if we could design a drug that would block the import of essential nutrient for the bacteria, we could starve it to death; or we could attempt to block the secretion of the virulent factors and let our immune system take care of the bacteria. During this project, information was gathered on the 3D structure of the T7SS complex machinery and, in collaboration with laboratories from Germany and France, more information was gathered on the factors secreted by T7SS and their impact on our immune system.
Data: CORDIS, © European Union
Project objective
Mycobacterium abscessus (Mab) is an opportunistic-multidrug-resistant non-tuberculous mycobacteria responsible for multiple clinically-acquired infections both pulmonary and extrapulmonary. Unlike many rapidly growing mycobacteria (RGM), Mab is able to survive and multiply within macrophages, similar to slow growing mycobacteria (SGM) such as M. tuberculosis (Mtb). In Mtb, five T7SS (ESX-1-5) have been identified and shown to be essential for intracellular survival (ESX-1), virulence (ESX-1 and ESX-5) or growth (ESX-3). T7SS are composed of five protein components essential for function: EccB, EccC, EccD, EccE and MycP. Except for a low-resolution structure of the holo ESX-5 complex from the host lab at 13 Å resolution, no structural data on any T7SS have been published to date, rendering structural work timely and eagerly awaited by relevant communities. Deemed inactive due to its lack of one of the established T7SS components EccE4, ESX-4 has been considered an ancestral T7SS form. However, Mab possess a fully intact and functional ESX-4, essential for its intracellular survival, rendering it a highly attractive target for an in-depth characterization. Here, I propose an interdisciplinary project that includes both functional and structural investigation. As the 2 M Dalton-holo-complex crosses the Mab inner membrane, experimental structural work will be challenging and require an integrative modeling approach to combine diverse experimental data sets. Complementary infection biology experiments including microbiology, genetics and cell biology will be carried out by collaborators. With this work, I aim to respond to central questions related to T7SS in general and Mab ESX-4 specifically, such as: what is the mechanism of T7SS-mediated secretion? What makes ESX-4 specific and different from other T7SS? What is the specific role of EccE4 to establish a functionally active ESX4? and What are the substrates and specific mechanism of ESX-4 substrate recognition?
Original text from CORDIS.
Participants
- EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergCoordinatorGermany
Links
Data: CORDIS, © European Union