TB-EURO-GEN

Genetic Analysis of the host-pathogen interaction in tuberculosis

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 Obiettivo del progetto (Objective)

'We propose to extend an existing collection of DNA extracts from TB patients and their corresponding TB DNA to establish the world’s largest resource of extracts from a population of TB patients and 5000 ethnically matched healthly controls. The bank will comprise 5000 DNA host DNA extracts paired the DNA and cultures of the strain of Mycobacterium tuberculosis causing their disease. We will perform a genome-wide scan to discover human genes predisposing to TB. We will then localise causal variants and study their role in a case-control population TB sample from another high incidence country in Africa ,Ghana. We will extensively characterise TB strains from a population in Russia using spoligotyping, minisatellite analysis, and SNP analysis of genes putatively associated with virulence and analyse the host-pathogen interaction identifying mycobacterial genes affecting the course of TB, the innate response to TB and outcome at a genetic level. Based on the existing collection of matched host-pathogen DNA we will perform functional experiments of the role of identified mycobacterial factors such as PE variants and the effect of this variation on aspects of innate immunity as influenced by newly-identified TB-associated genes.'

Introduzione (Teaser)

Despite the early promise of vaccines and antibiotics, tuberculosis is still spreading. A massive European study has begun to extend databases with bio-information on the TB mycobacterium responsible and genetic profiles of patients.

Descrizione progetto (Article)

One third of the world's population is thought to be infected with mycobacterium tuberculosis (TB) which causes the disease with the same name. Although most infections remain latent, one in ten develops an active infection.

Treatment of TB poses many problems. The existence of many strains, including antibiotic-resistant types, is one of the most important. Prevention relies on screening and immunisation with the Bacillus Calmette-Guerin (BCG) which is not 100;% effective.

Varying protection is gained from the BCG mainly because of genetic variability of both the bacterium and the population. Add to this the opportunistic nature of the disease, which takes advantage of the reduced immunity status of HIV sufferers, and two million deaths per year globally come as no surprise.

The EU-funded project TB-EURO-GEN is finding out why so many in a population can remain disease-free even though infected. The aim is to understand the relationship between the mycobacterium and the human host, and the genetic reasons for being susceptible to developing active TB. This they hope will lead to the discovery of genes for resistance to the disease.

To obtain meaningful data requires large trials. The TB-EURO-GEN team have already successfully recruited 5;000 people for a control group and 3;700 TB patients. The aim is to extend the number of patients to 5;000 and to extract their DNA as well as the infecting TB DNA.

Human DNA has also been collected from Ghana, another country with a high incidence of TB. The DNA is being analysed to isolate genes that predispose the patient to development of active TB.

State-of-the-art genetic techniques are being used to accumulate the vast amount of data. Through collaboration with the Sanger Institute in the UK, 200 M. tuberculosis strains have been analysed using a next-generation whole genome sequencing technique. Spolygotyping, a rapid yet accurate technique to analyse the genome, has been used on Euro-American and East Asian families to define the genetic ancestry of TB.

The matching of a statistically powerful number of samples from a multi-ethnic base is seen as the key to combating the growing problem of the disease. This promises to open up new possibilities for the development of vaccines and new targets for TB prevention.