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Novel Approaches to Determine Molecular Mechanisms of Pathogenesis in Tuberculosis

Objective

I initiated and developed an unbiased comprehensive study using whole genome array analysis of the transcriptome in blood of tuberculosis (TB) patients and provided global knowledge of the immune response and potential factors leading to TB pathogenesis. Using larger cohorts of TB patients and controls than previous studies, together with complementary analytical approaches of modular, pathway and gene level analysis, we identified a striking interferon (IFN)-inducible neutrophil-driven signature of active TB. This IFN-inducible gene signature correlated with extent of radiographic disease and was represented by Type I IFN as well as IFN-gamma-inducible genes. We propose to apply the knowledge obtained from our study of human TB to study in depth the potential role of Type I IFNs and Type I IFN-inducible genes in TB pathogenesis in susceptible genetic strains of mice infected with virulent Mycobacterium tuberculosis (MTb) strains. We propose to develop a modular tool to study complex transcriptional data in blood from mouse models of disease, as has been done for human disease, to allow accurate comparison of mouse models with human TB, and allow rapid analysis of the immune response at the transcriptional level to reflect pathogenesis, but also in the study of MTb-infected mice where potential pathways of pathogenesis have been perturbed. Based on our findings in human TB we propose to test the hypothesis that Type I IFN and genes induced by this pathway during TB, including Tripartite motif-containing proteins (TRIMs), are important determinants of pathogenesis. This will be achieved by their elimination or perturbation in susceptible TB models and in MTb-infected macrophages, dendritic cells, and neutrophils to define molecular mechanisms contributing to their role in TB pathogenesis.

Field of science

  • /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-2011-ADG_20110310
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

THE FRANCIS CRICK INSTITUTE LIMITED
Address
1 Midland Road
NW1 1AT London
United Kingdom
Activity type
Research Organisations
EU contribution
€ 1 522 491,41
Principal investigator
Anne O'garra (Dr.)
Administrative Contact
Stéphane Maikovsky (Mr.)

Beneficiaries (2)

THE FRANCIS CRICK INSTITUTE LIMITED
United Kingdom
EU contribution
€ 1 522 491,41
Address
1 Midland Road
NW1 1AT London
Activity type
Research Organisations
Principal investigator
Anne O'garra (Dr.)
Administrative Contact
Stéphane Maikovsky (Mr.)
MEDICAL RESEARCH COUNCIL
United Kingdom
Address
North Star Avenue Polaris House 2 Floor David Phillips Building
SN2 1FL Swindon
Activity type
Research Organisations
Administrative Contact
David Jones (Mr.)