Genetic diversity driving drug-resistant TB

The evolutionary secrets of the bacterium that causes tuberculosis (TB) could help address the public health emergency posed by drug-resistant TB.

Mycobacterium tuberculosis, infects around one third of the world’s population and one person dies from the disease every 15 seconds.

The world-wide emergence of multi-drug resistant strains of M. tuberculosis is making TB increasingly difficult to treat and control.

At the MRC’s National Institute for Medical Research Dr Sebastien Gagneux is looking for clues to address the growing threat by studying the pathogen’s evolution.

In research published in PLoS Biology, Dr Gagneux and his collaborators show that the different strains of bacterium that cause TB, collectively known as the M. tuberculosis complex (MTBC), are more genetically diverse than previously assumed. And that this variety in genetic arrangement could make drug-resistance worse. Consider the additional impact of human behaviours like global travel and city living and the ability to treat TB with existing drugs is further diminished.

Little is known about the extent of genetic diversity in TB bacteria nor the evolutionary forces that shape it. To learn more, the research team studied a collection of 99 human tuberculosis strains using DNA sequencing.

Dr Gagneux explains: ‘‘We compared the genetic distances between different strains of the bacterium that causes TB from around the world. Overall the analysis reveals greater genetic diversity in the bacteria adapted to infect humans than previously appreciated. The diversity can be linked to changes in human demography and to both ancient and recent human migrations. It’s an out-of-and-back-into Africa scenario.’’

The study identified genetic drift, the process by which random changes in DNA accumulate over generations, as a possible evolutionary force driving diversity in MTBC. The other important factor is reduced selection pressure. The bacteria often exist in divided populations each started by a different original bacterium within the same lung because one cell is enough to establish an infection. As it multiplies each new bacterium is a copy of the original so exchange of genes with other strains is rare. Random genetic drifts allow mutations to reach high frequencies and in an organism that needs a large population to cause disease these changes would normally be removed by natural selection. However, in the small population sizes of MTBC infection the effect of random genetic drifts is increased compared to that of natural selection.

Much of the genetic diversity in MTBC could affect how well new TB diagnostics, drugs and vaccines work.

Commenting on progress in understanding MTBC genetic diversity Dr Gagneux said: ‘‘Our future research will include using the new DNA sequencing technologies that are becoming available to further study the evolution of TB in different parts of the world, particularly in Africa, India and more remote places like Papua New Guinea and the Amazon. We plan to tackle the question ‘how are different variants of TB perceived by the human host?’ We will also study the consequences of this genetic diversity for the host-pathogen interaction.’’

(Source: Medical Research Council UK: January 2009)