January, 10th 2006
Identification of a new human genetic factor involved in susceptibility to tuberculosis
Teams from the Institut Pasteur and the CNRS have just identified a new human genetic factor involved in susceptibility to tuberculosis. Researchers analysed the extent to which variability of the DC-SIGN gene could be involved in susceptibility to become sick after Mycobacterium tuberculosis infections, in a large South African population. They showed that a variant of this gene is over-represented in individuals who do not develop the disease. This research, published in PLoS Medicine, should help in understanding the role of DC-SIGN in the spread of tuberculosis, and in providing avenues to develop new strategies for treating the disease.
Tuberculosis—one of the major infectious causes of death for both youths and adults—kills around two million people every year across the world. However, even though close to two billion people are infected by the bacterium, only ten percent of them develop the disease. The reasons for differences in individuals’ sensitivity to this infection vary, including their age, the quality of their diet, the presence of other infections, the virulence of the strain of Mycobacterium by which they are infected, as well as genetic factors of susceptibility.
Recently, a team from the Institut Pasteur demonstrated the role of DC-SIGN as a key receptor for Mycobacterium tuberculosis in TB patients (1). In the work here presented, Lluis Quintana-Murci’s team in the Molecular Prevention and Therapy of Human Diseases Unit (Institut Pasteur-CNRS) attempted to find out whether genetic variants of DC-SIGN could influence the susceptibility of individuals infected by Mycobacterium tuberculosis to develop tuberculosis-disease.
To do this, they screened the DNA of a group of volunteers from South Africa, both with TB and without it. They noticed that a particular variant of the gene coding for DC-SIGN was significantly over-represented in individuals without TB. Given the great likelihood that the large majority of these people had been in contact with the bacterium, which is endemic in the region, the authors concluded that this variant of the gene could take part in protecting humans against the disease.
Furthermore, they showed that this variant is more present in Eurasian populations than in African populations. This difference could be explained by the fact that over the course of history, Eurasian populations would have been exposed to the TB bacillus earlier, and possibly to other pathogens likely to be linked to DC-SIGN as well. This exposure over time would have led to an earlier selection of protective variants in Eurasian populations.
For the past few years, the key role of DC-SIGN in the pathogenesis of several infectious diseases (AIDS, Ebola, cytomegalovirus, hepatitis C, dengue, and so on) has been demonstrated. All of the data presented here stresses once again the essential role that DC-SIGN plays in controlling the spread of tuberculosis. A better understanding of this role should eventually make it possible to help improve treatments against these pathogens.
(1) Ludovic Tailleux and Olivier Neyrolles, in the Unité de Génétique Mycobactérienne directed by Brigitte Gicquel et the Institut Pasteur. Tailleux et al. 2005. DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis. PLoS Med, 2(12) e381.
Luis B Barreiro (1,2), Olivier Neyrolles (2), Chantal L Babb (3), Ludovic Tailleux (2), Hélène Quach (1), Ken McElreavey (4), Paul D van Helden (3), Eileen G Hoal (3), Brigitte Gicquel (2), Lluís Quintana-Murci (1)
1. Unité de Prévention et Thérapie Moléculaires des Maladies Humaines Institut Pasteur-CNRS FRE 2849
2. Unité de Génétique Mycobactérienne, Institut Pasteur, Paris
3. Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa Division of Nephrology, Mayo Foundation, Rochester, Minnesota, USA
4. Unité Reproduction, Fertilité et Populations, Institut Pasteur, Paris, France
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