Search

 

PressCNRS international magazine

Table of contents

Genetics

Genetic assets to resist tuberculosis

There are still eight million new cases worldwide of tuberculosis infection recorded every year. But of those infected, only 10% end up developing the disease. Scientists have now identified particular genetic characteristics in hosts that could make them vulnerable towards the pathogen.

tuberculose

© P. Gounon/Institut Pasteur

Mycobacterium tuberculosis, the bactirium that causes most cases of tuberculosis.


 

Researchers from the Pasteur Institute and CNRS in Paris, with their colleagues in South Africa, have recently discovered that a specific variation in a gene involved in immunity seems to affect an individual's susceptibility to develop tuberculosis.1 Furthermore, this variation is not equally distributed among the world's different ethnic groups.

When Mycobacterium tuberculosis (the bacillus responsible for tuberculosis) infects its host, it most often settles in the lungs, sometimes in the bones, the kidneys or in the lymph nodes. It can remain there in a “sleeping” state for years, until the host's immune system is weakened–due to malnutrition, disease, or physiological changes like pregnancy. At this point, the body can no longer find the resources to repress the bacteria, which becomes active–and the disease breaks out.

The recent appearance of strains resistant to existing medications has caused the number of deaths to skyrocket to about 1.9 million a year. These cases occur mostly in Sub-Saharan African regions, where the estimated incidence per capita is nearly twice that of South-East Asia, according to the World Health Organization.

“This high incidence could be due to more than the high prevalence of HIV infection and malnutrition in these countries, it could also be related to different genetic susceptibility” says Dr. Lluis Quintana-Murci, from the Unit of Molecular Prevention and Therapy of Human Diseases at the Pasteur Institute.2 Three years ago, the bacillus's major receptor cell was identified–a protein called DC-SIGN, also involved in the reconnaissance of other pathogens including the HIV and Ebola viruses. DC-SIGN was already widely known for its role in innate immunity, the human host's first line of defense.

The importance of this reconnaissance protein is reflected in the highly-conserved sequence of its gene–CD209–in different human populations. “This gene has remained very constant throughout history because it acts as an important defense mechanism against pathogens” states Quintana-Murci. “It cannot afford 'the luxury' of mutating to change the resulting protein.” He therefore hypothesizes that genetic variation in CD209 might have important repercussions on an individual's resistance to tuberculosis.

The researchers chose to work on a population from Cape Town, South Africa, which has some of the world's highest incidence rates of infection by M. tuberculosis. They sequenced and compared the CD209 gene in a cohort of individuals, where half of the participants had tuberculosis, and the other half did not. Because tuberculosis is so common in this region, it is highly likely that both sick and healthy individuals had been infected with M. tuberculosis at some point.

The team's findings, recently published in PLoS Medicine, reveal that a combination of two specific alleles of CD209 seems very influential in lowering susceptibility to develop tuberculosis. The protective combination was found in 9% of tuberculosis patients, compared to 14% of healthy controls. “This difference is highly significant and shows that the protective variants are more represented in healthy individuals than in tuberculosis patients” says Quintana-Murci. In order to assess the prevalence of this genetic variation on a wider scale, the team searched for its presence in a group of individuals from Europe, Asia, and Africa. Their analysis showed that Africans were much more likely to lack the allelic combination than individuals from Europe and Asia. “It seems that over time, M. tuberculosis has exerted a stronger selective pressure on European and Asian populations, as compared to African ones.” This is not surprising since there is fairly convincing evidence that tuberculosis has been endemic in Europe for several hundred years, whereas it was probably rare in Africa before contact with Europeans.

A better understanding of the host's genetic susceptibility should in time lead to improvements in fighting tuberculosis.

 

Clémentine Wallace

Notes :

1. Barreiro LB et al., “Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis,” PLoS Med. 3 (2): e20. 2006.
2.Unité de Prévention et Thérapie Moléculaires des Maladies Humaines (CNRS / Institut Pasteur joint lab).


Contacts :

Lluis QUINTANA-MURCI
Institut Pasteur, Paris.
quintana@pasteur.fr


Top

Back to homepageContactcredits