Spatiotemporal regulation of localization and replication of M. tuberculosis in human macrophages

Informacje na temat projektu

DynaMO_TB

Identyfikator umowy o grant: 772022

DOI

10.3030/772022

Projekt został zamknięty

Data podpisania przez KE 30 Stycznia 2018

Data rozpoczęcia 1 Września 2018

Data zakończenia 31 Sierpnia 2024

Finansowanie w ramach

• EXCELLENT SCIENCE - European Research Council (ERC)

Koszt całkowity

€ 2 000 000,00

Wkład UE

€ 2 000 000,00

Koordynowany przez

THE FRANCIS CRICK INSTITUTE LIMITED
United Kingdom

Periodic Reporting for period 4 - DynaMO_TB (Spatiotemporal regulation of localization and replication of M. tuberculosis in humanmacrophages)

Okres sprawozdawczy: 2023-03-01 do 2024-08-31

Podsumowanie kontekstu i ogólnych celów projektu

Tuberculosis (TB) caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb) remains one of the deadliest infectious diseases with over a billion deaths in the past two hundred years (Paulson, 2013). TB causes more deaths worldwide than any other single infectious agent, with 1.25 million deaths in 2023 (WHO TB Report). The obstacles that make TB hard to treat and eradicate are intrinsically linked to the intracellular lifestyle of Mtb. Mtb needs to replicate within human cells to disseminate to other individuals and cause disease. However, we still do not completely understand how Mtb manages to survive within eukaryotic cells and why some cells are able to eradicate this lethal pathogen. In this project, developed cutting-edge imaging technologies, such as live cell imaging, super resolution microscopy and correlative live cell 3D- electron microscopy, capable of imaging and quantifying Mtb localisation and replication.

Prace wykonane od początku projektu do końca okresu sprawozdawczego oraz najważniejsze dotychczasowe rezultaty

We established the production and differentiation of human iPSC-derived macrophages (iPSDM) and extensively characterised these cells as a model to study tuberculosis. This analysis includes RNA-seq gene expression analysis after infection with Mycobacterium tuberculosis and extensive phenotyping. There is now a high content single cell imaging platform in BSL3 that is currently used for data acquisition/analysis in M. tuberculosis infected iPSDM.
Using this human macrophage model, we have been investigating the role of the mitochondria and metabolism during infection of human macrophages with M. tuberculosis. We found that infection with M. tuberculosis induces a striking reprogramming of macrophage metabolism, and this is dependent on the M. tuberculosis Type 7 Secretion System (T7SS). We also discovered a new role for stress granules (SG) in the function of human macrophages during infection. Finally, we revealed a role for peroxisomes in the innate immune response to M. tuberculosis.

Innowacyjność oraz oczekiwany potencjalny wpływ (w tym dotychczasowe znaczenie społeczno-gospodarcze i szersze implikacje społeczne projektu)

In the last six years my lab has significantly contributed to our understanding of the host-pathogen interactions in TB primarily in three main areas: (1) the impact of the Mtb intracellular lifestyle on chemotherapy, we developed cutting-edge imaging approaches to visualise antibiotics at the subcellular level. These studies have shown that cellular metabolic states of infected cells, such as lipid droplet content, affect antibiotic efficacy. (2) Mtb induces endomembrane damage during infection, and it is clear this phenomenon has profound consequences for the pathogenesis of TB. Our work has identified several mechanisms/pathways that are implicated in the host repair mechanisms of membrane damage induced by Mtb in macrophages and (3) we have established the use of human induced pluripotential stem cells (iPSC) models to study innate immune mechanisms in human macrophages at the molecular and cellular level and combine these technologies with lung on chip approaches to mimic human alveolar environments.

Mtb infecting macrophages