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Virulence of TB strain in Leicester outbreak caused by ‘unusual’ mechanism

Scientists have identified a mechanism that contributes to the virulence of a particular strain of tuberculosis, making it appear more likely to lead to disease than other strains. In 2001, this strain, known as CH, was responsible for a major school outbreak of TB in Leicester thought to have infected at least 254 pupils.

In general, most people infected with Mycobacterium tuberculosis, the bacterium that causes TB, will not show any symptoms. It is thought that one third of all people carry the bacteria, yet less than one in ten will develop TB. However, almost a quarter of the people infected with the CH strain required treatment for the disease. Left untreated, TB can prove fatal.

Now, a team jointly led by Dr Robert Wilkinson at the Wellcome Trust Centre for Clinical Tropical Medicine, Imperial College London, and Professor Mike Barer at the University of Leicester, has identified a segment of the CH genome which, when absent, modifies the immune system’s response to the strain and make it more likely to lead to disease. The findings of their research are published today in Proceedings of the National Academy Sciences of the USA. The research was funded by the Wellcome Trust and the Medical Research Council.

“Whilst this particular strain of TB does not appear more infectious than others, it appeared more likely to cause primary disease and endanger the health of an infected person,” says Dr Wilkinson. “The CH strain has evolved a mechanism to avoid the early immune response and thus give it an advantage in the early struggle against the immune system. Interestingly the genetic basis for this appears to be the loss, rather than gain, of a gene, which is unusual.”

The missing segment is thought to be have been deleted during a rare rearrangement within the CH genome.

“TB and other mycobacteria appear to be remarkably careless about preserving their genomes and appear to have evolved by a succession of ‘accidents’ in which several genes have been lost at a time,” explains Professor Barer. “We don't really understand how the losses occur, but it is likely that, for one reason or another, loops form in the DNA and the genes in the loops are lost.

“Unlike many other bacteria, the TB group cannot pick up DNA from its relatives so it cannot get lost genes back again. The ultimate example of this is the leprosy bacillus. This has lost so many genes that it can now only grow in the tissues of humans, nine-banded armadillos and immunocompromised mice.”

Despite the increased likelihood that the CH strain of tuberculosis will develop to the disease stage, Dr Wilkinson is keen to stress that it is still possible to treat the strain.

“Although this strain appears more likely to lead to disease than others, it is responsive to the antibiotics prescribed for TB infection,” says Dr Wilkinson.

Professor Barer comments: “Our studies on the TB outbreak strain seem to have uncovered a deeper truth about how the bacterium may evolve and adapt to persist in different human populations.”

According to the Health Protection Agency, the incidence of TB in the UK is increasing, but it still remains quite rare, with less than 7000 new cases a year. Cases in the UK are predominantly confined to the major cities and about 40% of all cases are in London. However, globally TB is a major problem: an estimated one third of the world's population – nearly two billion people – are infected. Ten million people a year develop the active disease worldwide, which kills three million each year.

Alex Jelley | alfa
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