Scientists have moved a step closer to developing a blood test that one day will be able to predict which 10 per cent of people who carry the TB bacterium in a latent form will later go on to have the full blown disease: they have identified clusters of genes or a “transcriptional signature” in patients with latent TB that is also carried by people with the active disease.

You can read about the research behind this finding in a paper published online in the journal Nature on 19 August. The lead author was Dr Matthew P. R. Berry, from the Division of Immunoregulation at the Medical Research Council (MRC), in London, UK. Other authors were also from the MRC, and other research establishments in the UK, South Africa, and the US.

Tuberculosis or TB, most of which is caused by the bacterium Mycobacterium tuberculosis, is a major cause of disease and death worldwide.

There are two forms of TB: latent and active. People with the latent form of the disease carry the bacterium but don’t develop symptoms, in fact only 10 per cent of people with the latent form will go on to develop the active form. The active disease attacks mainly the lungs, but TB bacteria can also attack any part of the body such as the kidney, spine, and brain.

Unfortunately, our immune response to the bacterium is not straightforward and difficult to characterize. This is what has been holding back the development of new diagnostics, treatments and vaccines. It appears that susceptibility to the disease is not a matter of one or two genes, but clusters of genes, and maybe even relationships between those clusters, controlled by whether certain genes are switched on or off.

So currently, while we can test whether people carry the TB bacterium, we can’t tell which of the 1 in 10 carriers is likely to progress to active disease.

Using a “systems-biology” approach, Berry and colleagues compared the genes of patients with active and latent tuberculosis (TB) with those of healthy controls who had neither latent nor active TB.

The approach they used enabled them to search for what is known as a “transcriptional signature” of expressed genes, or in other words, particular clusters of switched on genes that are common to people with the active and the latent forms of TB, but not in people who don’t carry either forms.

This way they hoped to home in on which of those clusters are the most likely to contain predictive biomarkers of the disease, which can then be used to test people who have the latent form and predict whether they will go on to develop the active form.

They found that one particular blood-based signature, the “neutrophil-driven interferon (IFN)-inducible gene profile”, was the strongest link between people with latent TB and those with active disease, and this “reverted back to that of healthy controls after treatment”.

They also found that a subset of this signature discriminated active TB from other inflammatory and infectious diseases, and that while an “IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB”.

They concluded that their study had found a hitherto unappreciated role for the type of signalling this signature controls in the development of TB and this could be important for developing new vaccines and treatments.

“Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic,” wrote Berry and colleagues.

Study leader Dr Anne O’Garra of the MRC’s National Institute for Medical Research, said:

“If you could predict which so-called carriers of TB will progress to the full-blown disease, this would have major ramifications for stopping the global epidemic.”

“We just have to prove it now, but it’s very promising,” she told the BBC.

“An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.”
Matthew P. R. Berry, Christine M. Graham, Finlay W. McNab, Zhaohui Xu, Susannah A. A. Bloch, Tolu Oni, Katalin A. Wilkinson, Romain Banchereau, Jason Skinner, Robert J. Wilkinson, Charles Quinn, Derek Blankenship, Ranju Dhawan, John J. Cush, Asuncion Mejias, Octavio Ramilo, Onn M. Kon, Virginia Pascual, Jacques Banchereau, Damien Chaussabel & Anne O’Garra.
Nature, Volume 466, Pages 973-977, published 19 August 2010.

Additional sources: CDC, BBC.

Written by: Catharine Paddock, PhD