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CORDIS

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

Project description

A genome-wide screen for novel therapeutic targets against tuberculosis

Tuberculosis is a global health issue exacerbated by the emergence of drug-resistant pathogens. Understanding the host–pathogen interaction is necessary for the development of novel host-directed therapies that augment the capacity of the immune system to fight Mycobacterium tuberculosis (Mtb). The EU-funded Host-TB project will use the CRISPR editing technology to perform a genome-wide screen on human macrophages infected with Mtb. The key objective is to identify genes implicated in the interaction with the pathogen as well as comprehensively characterise the associated pathways. The project's results have the potential to lead to the identification of novel therapeutic targets against tuberculosis.

Objective

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 (HDTs) can improve immune mechanisms by augmenting the ability of host cells to kill M. tuberculosis (Mtb) or by modulating the immune response to prevent excessive inflammation, cell death and tissue damage. Progress with HDT development has been slowed down by the limited understanding of host-pathogen interactions during Mtb infection. Screens of the whole human genome can identify novel genes involved in the immune responses to Mtb 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 for the first time use the groundbreaking CRISPR technology to screen the human genome in macrophages infected with Mtb and discover genes that are critically involved in host-pathogen interactions. Then, we will comprehensively characterise pathways that mediate impacts of these genes on both the human macrophage and the intracellular Mtb bacilli using dual transcriptome analyses and high-throughput microscopy assays. This novel approach will dissect crucial mechanisms of host-pathogen interaction during Mtb infection and will point to new targets for HDTs of TB.

Keywords

Host institution

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Net EU contribution
€ 1 366 940,49
Address
TRINITY LANE THE OLD SCHOOLS
CB2 1TN Cambridge
United Kingdom

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Region
East of England East Anglia Cambridgeshire CC
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 366 940,49

Beneficiaries (2)