Using CRISPR genome screens and dual transcriptome analyses to dissect host-pathogen interactions in tuberculosis

Informacje na temat projektu

Host-TB

Identyfikator umowy o grant: 832721

DOI

10.3030/832721

Projekt został zamknięty

Data podpisania przez KE 18 Kwietnia 2019

Data rozpoczęcia 1 Czerwca 2019

Data zakończenia 31 Maja 2026

Finansowanie w ramach

• EXCELLENT SCIENCE - European Research Council (ERC)

Koszt całkowity

€ 2 160 926,00

Wkład UE

€ 2 160 926,00

Koordynowany przez

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 4 - Host-TB (Using CRISPR genome screens and dual transcriptome analyses to dissect host-pathogen interactions in tuberculosis)

Okres sprawozdawczy: 2023-10-01 do 2025-03-31

Podsumowanie kontekstu i ogólnych celów projektu

With more than 10 million cases annually, tuberculosis (TB) remains a global health problem. TB epidemic is exacerbated by the spread of multidrug-resistant TB. Host-directed therapies can improve immune mechanisms by augmenting the ability of host cells to kill M. tuberculosis bacilli or by modulating the immune response to prevent excessive inflammation, cell death and tissue damage in the human body. Progress with the development of new host-directed therapies has been slowed down by the limited understanding of host-pathogen interactions during M. tuberculosis infection. Screens of the whole human genome can identify novel genes involved in the immune responses to M. tuberculosis infection and susceptibility to TB. Previously, we successfully used genome-wide association studies to identify human genes associated with susceptibility to TB. Here, we will use the groundbreaking CRISPR technology to screen the human genome in macrophages infected with M. tuberculosis and discover genes that are critically involved in host-pathogen interactions. Then, we will comprehensively characterise cellular signalling pathways that mediate impacts of these genes on both the human macrophage and the intracellular bacilli using dual transcriptome analyses and high-throughput microscopy assays. This novel approach will dissect crucial mechanisms of host-pathogen interaction during M. tuberculosis infection.

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

We performed the screens of human genome in CRISPR-Cas9-edited macrophages after their infection with M. tuberculosis. These screens revealed several genes that regulate death of human macrophages during infection.

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

The novel human genes that affect susceptibility of macrophages to M. tuberculosis infection will be now validated in the follow-up experiments. Details of the mechanism of macrophage death will be thoroughly characterised for each of the newly identified genes and the role of virulence factors of M. tuberculosis will be also studied. Proteins encoded by these genes and their signalling pathways may provide novel targets for host-directed therapy of tuberculosis.

Human macrophages engulfing mycobacteria