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

Field of science

  • /natural sciences/biological sciences/genetics and heredity/genome
  • /medical and health sciences/health sciences/public and environmental health/epidemics prevention/immunisation
  • /medical and health sciences/clinical medicine/pneumology/tuberculosis

Call for proposal

ERC-2018-ADG
See other projects for this call

Funding Scheme

ERC-ADG - Advanced Grant

Host institution

STICHTING VUMC
Address
De Boelelaan 1117
1081 HV Amsterdam
Netherlands
Activity type
Research Organisations
EU contribution
€ 1 417 662,50

Beneficiaries (2)

STICHTING VUMC
Netherlands
EU contribution
€ 1 417 662,50
Address
De Boelelaan 1117
1081 HV Amsterdam
Activity type
Research Organisations
THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom
EU contribution
€ 743 263,50
Address
Trinity Lane The Old Schools
CB2 1TN Cambridge
Activity type
Higher or Secondary Education Establishments