MTB-DETOX · Molecular Mechanisms for Host-Mediated Metal Poisoning Detoxification in Mycobacterium tuberculosis
„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“
- Период
- 2022-09-01 → 2024-08-31
- Финансиране от ЕС
- 195 915 €
- Участници
- 3
- Схема
- HORIZON-TMA-MSCA-PF-EF
Линиите свързват координатора с партньорите.
Накратко на български
Механизмите, чрез които бактерията Mycobacterium tuberculosis изхвърля излишни метали като цинк, за да оцелее в човешките клетки, са в центъра на анализа. Разбирането на тези процеси помага при търсенето на нови мишени за разработване на лекарства срещу туберкулозата.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Molecular Mechanisms for Host-Mediated Metal Poisoning Detoxification in Mycobacterium tuberculosis
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), claims 1.5 million lives annually. Upon inhalation, Mtb reaches the alveoli of the lungs, where it is engulfed by macrophages and enclosed in phagosomes, specialized vacuoles designed to degrade pathogens. Inside the phagosome, Mtb is exposed to various stresses, including nutrient deprivation, hypoxia, reactive oxygen and nitrogen species, and acidification. Despite these hostile conditions, Mtb is an exceptionally resilient pathogen, having evolved mechanisms to survive and persist within its host. In a seminal study (PMID: 21925112), our lab discovered the accumulation of zinc within macrophage phagosomes during Mtb infection, leading to the identification of a novel zinc detoxification system in Mtb. This system consists of a membrane pump, CtpC, and a previously unknown metallochaperone, PacL1, which is essential for stabilizing CtpC (PMID: 35961955). Our research demonstrated that the PacL1/CtpC system is critical for Mtb replication within macrophages, suggesting that bacterial metal detoxification mechanisms represent promising targets for novel drug development. Mtb possesses two additional homologous systems to PacL1/CtpC, named PacL2/CtpG and PacL3/CtpV. While CtpV has been implicated in copper tolerance, the role of CtpG remains unclear. Furthermore, the biological functions of PacL2 and PacL3 in Mtb were completely unknown. The first objective of my project was to investigate the involvement of the PacL2/CtpG and PacL3/CtpV systems in metal detoxification and pathogen survival during infection, as well as to elucidate the specific roles of the uncharacterized PacL2 and PacL3 proteins. Preliminary findings from our laboratory revealed that PacL1, PacL2, and PacL3 colocalize in dynamic patches at the plasma membrane, suggesting the existence of uncharted metal efflux platforms composed of multiple metal chaperones (PacL proteins) and efflux pumps (Ctp proteins). However, the structure, composition, and dynamics of these platforms, along with the potential impact of their formation on efflux efficiency, remained completely unknown. Therefore, the second objective of my project was to characterize the composition and dynamics of these uncharted structures and to explore the collaborative functions of the PacL1/CtpC, PacL2/CtpG, and PacL3/CtpV systems.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) kills 1.5 million people every year. Major challenges facing TB eradication are the lack of effective and affordable treatments, the slow pace of innovation in TB drug discovery and the emergence of antibiotics resistance. Therefore, new approaches for addressing these challenges are urgently needed. Mtb is highly adapted to survive into human macrophages which expose the bacterium to many stresses including metal ion in-toxification, whereby the host cell increases its metal ion levels resulting in inflow of metal ions into Mtb. The host laboratory has previously demonstrated that the P-ATPase transporter CtpC is part of the metal efflux system involved in zinc detoxification, which is important for Mtb survival in macrophages. Intriguingly, CtpC and two other P-ATPases are encoded together with small proteins containing a domain of unknown function named DUF1490. Unpublished data show that the DUF1490 protein encoded with CtpC binds zinc and confers zinc in-toxification tolerance to Mtb. Additionally, DUF1490 proteins co-localize with CtpC to the plasma membrane into dynamic microdomains, named “metal efflux platforms”. I propose to uncover the function of DUF1490 proteins by testing two hypotheses: 1) DUF1490 proteins are metallochaperones that facilitate the intracellular transport of metal ions to membrane transporters, and 2) DUF1490 proteins are scaffold proteins involved in P-ATPase stabilization and metal efflux platforms assembly. To explore these hypotheses, I will combine genetic, microbiology and molecular biology strategies with high-resolution optical imaging, lipidomics and proteomics. Rigorous execution of the proposed research will generate insights into the role of DUF1490 proteins in Mtb metal detoxification and pathogenicity, as well as into the novel concept of metal efflux platforms, thus yielding opportunities for TB drug development that go beyond traditional targets.
Оригинален текст от CORDIS (на английски).
Участници
Връзки
- Виж в CORDIS
- DOI: 10.3030/101063199
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e502fa9cea&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5100d87d2&appId=PPGMS
Данни: CORDIS, © Европейски съюз