Description du projet
Une nouvelle approche pour évaluer la réponse du bacille de Koch aux antibiotiques
Le bacille de Koch (BK) est l’agent responsable de la tuberculose qui provoque des millions de décès chaque année dans les pays d’Asie et d’Afrique. Les efforts continus fournis pour développer de nouveaux traitements plus efficaces soulignent la nécessité de comprendre comment l’environnement intracellulaire affecte la réponse du bacille de Koch aux antibiotiques. Le projet SpaTime_AnTB, financé par l’UE, propose d’étudier les mécanismes qui permettent au bacille intracellulaire de répondre aux antibiotiques dans les cellules hôtes en recourant à des technologies d’imagerie de pointe. Les découvertes du projet apporteront des informations essentielles sur la biologie du bacille de Koch et identifieront les déterminants spatiaux et métaboliques de la réponse au médicament, ouvrant ainsi de nouvelles voies pour la conception d’interventions thérapeutiques.
Objectif
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.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
NW1 1AT London
Royaume-Uni