SpaTime_AnTB · Single-cell spatiotemporal analysis of Mycobacterium tuberculosis responses to antibiotics within host microenvironments
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2020-04-01 → 2022-03-31
- Финансиране от ЕС
- 224 934 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Разпределението на антибиотиците в човешките макрофаги се анализира чрез високоразрешаваща микроскопия, за да се види как бактериите Mycobacterium tuberculosis реагират на тях. Това помага за разработването на по-кратки и ефективни схеми за лечение на туберкулозата.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Single-cell spatiotemporal analysis of Mycobacterium tuberculosis responses to antibiotics within host microenvironments
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health issue and one of the deadliest diseases caused by a single infectious agent worldwide. Drug-sensitive TB requires treatment with a minimum of four antibiotics over a course of at least 6 months. The duration and toxicity of the current anti-TB regimens affect compliance, leading to treatment failure, relapse and emergence of resistant strains which constitute a real challenge. Therefore, the design of new drug regimens or alternative therapeutic strategies are desperately needed to reduce treatment duration and ultimately eradicate TB. In that context, understand how lung physiopathology and microenvironments affect antibiotic distribution, accumulation and efficacy is crucial, specially within macrophages, that represent one of the principal niches for Mtb survival and replication during infection. In this project entitled SpaTime_AnTB, we aimed at (i) implementing robust and innovative high-resolution quantitative microscopy approaches, in order to visualize the spatial distribution of antibiotics within infected human macrophages, (ii) determine how multiple intracellular niches and their respective microenvironments impact the accumulation and efficiency of antibiotics, and finally (iii) develop a model of host-pathogen interaction based on the use bacterial reporter strains, subcellular compartments labeling techniques and real-time microscopy approaches to define Mtb responses to different subcellular compartments in the presence or absence of front-line drugs.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is an intracellular pathogen that killed 1.6 million people in 2017. Despite its enormous relevance for TB treatment, how intracellular environments affect the response of Mtb to antibiotics remain poorly characterised. This gap in knowledge is mainly due to the lack of appropriate technologies that have precluded comprehensive understanding of the response of intracellular pathogens to antibiotics, critical to design rational interventions. Here, I propose to use cutting-edge imaging approaches to define: (i) Mtb responses towards specific host-subcellular microenvironments by single-cell live long-term imaging in infected human stem cell-derived macrophages (iPSDM); (ii) the dynamics of antibiotic-mediated killing mechanisms using mycobacterial fluorescent reporters and high resolution correlative microscopy and (iii) the spatial and metabolic features of the Mtb response to antibiotics in vivo using a TB mouse model.For this, I will capitalise on technologies developed in the host group to quantify Mtb localisation and replication at the single-cell level combined with correlative electron microscopy (CLEM and CLEIM) approaches. This project will challenge the current limits of high content imaging by combining iPSDM with micro-patterning technologies for single-cell analysis. This will allow the identification of Mtb responses to antibiotics in host cells and how different intracellular microenvironments impact this process in cellulo and in vivo. Together, this proposal has the potential to uncover novel mechanisms of action of antibiotics in human macrophages, opening new avenues for a deeper understanding of human TB treatment and facilitate the discovery of new antibiotics.
Оригинален текст от CORDIS (на английски).
Участници
- THE FRANCIS CRICK INSTITUTE LIMITED · LondonКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз