H2020Индивидуална стипендия2021–2023

CryoMyco · Atomic dissection of type VII secretion systems from pathogenic mycobacteria

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-04-01 → 2023-03-31
Финансиране от ЕС: 174 806 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Секреторните системи от тип VII при микобактериите изследват как протеини и вредни фактори преминават през защитната обвивка на бактерията. Разбирането на този механизъм помага в борбата с опасни заболявания като туберкулозата и прогзата.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Atomic dissection of type VII secretion systems from pathogenic mycobacteria

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.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Tuberculosis (TB) is a global disease. With over 1.6 million deaths in 2017 alone and an estimated one quarter of the world’s population infected with Mycobacterium tuberculosis (Mtb), the etiological agent, TB is found throughout the world. Mtb is highly successful as a pathogen, in part due to its distinct and hydrophobic outer membrane (OM) and its type VII secretion systems (T7SSs). Although critical for the success of Mtb as a pathogen, the structure and mechanism of T7SSs are still poorly understood. In Mtb, five T7SSs (ESX-1 to 5) perform diverse functions such as immunomodulation, virulence, uptake of nutrients and iron. In T7SSs, four conserved membrane components, EccB/C/D/E assemble into a hexameric inner membrane complex, with a fifth transiently interacting membrane component, MycP. We have previously shown a low resolution, hexameric structure of the EccB/C/D/E membrane complex and recently two models of a dimeric subcomplex have been published. However, little is known on the structure of the entire core complex (including MycP), what is the secretion pore and how is it gated, or how secretion takes place through the OM, making this research proposal timely and necessary. The aim of this fellowship is to elucidate the underlying mechanism of secretion through the diderm cell envelope by: 1 - Elucidating the high-resolution structure of the hexameric T7SS membrane complex of Mtb. 2 - Investigate the molecular and structural mechanisms behind the OM translocation process. The results stemming from this proposal have the potential to aid and steer structure-based drug designs against Mtb. The host lab has pioneered cryo-EM of secretion systems and has state-of-the-art infrastructure and know-how that will provide the fellow with the best possible training and chances of success. With appropriate measures put in place, this project will drive forward mycobacterial research and will serve as a starting platform for identifying new possible drug targets.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF · HamburgКоординаторГермания