Descrizione del progetto
Un nuovo approccio per calibrare la risposta del Mycobacterium tuberculosis agli antibiotici
Il Mycobacterium tuberculosis è l’agente che provoca la tubercolosi, responsabile ogni anno di milioni di decessi nei paesi asiatici e africani. Gli sforzi continui per lo sviluppo di trattamenti nuovi e più efficaci sottolineano la necessità di comprendere in che modo l’ambiente intracellulare condiziona la risposta dei micobatteri agli antibiotici. Il progetto SpaTime_AnTB, finanziato dall’UE, propone di studiare i meccanismi attraverso cui i micobatteri intracellulari rispondono agli antibiotici in cellule ospiti utilizzando tecnologie di imaging all’avanguardia. I risultati del progetto forniranno una conoscenza essenziale sulla biologia del micobatterio e identificheranno le determinanti spaziali e metaboliche della risposta ai farmaci, aprendo nuove strade alla progettazione di interventi terapeutici.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
NW1 1AT London
Regno Unito