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Study Identifies Genetic Signature for TB Prognosis

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A team led by scientists at the UK Medical Research Council's National Institute for Medical Research has uncovered a genetic signature in tuberculosis patients' blood that could eventually lead to the development of a prognostic test for the disease.

"This discovery could not only serve as the basis of future diagnostic tests but also sheds light on why some people go on to develop active TB disease," MRC said in a statement following the publication of the study in Nature this week.

Experts estimate that although one-third of the world's population has been exposed to Mycobacterium tuberculosis, the organism that causes TB, they show no symptoms of carrying the infection. Only around one in 10 carriers will develop full-blown TB over their lifetime.

Standard methods for detecting the latent form of the disease include a skin test or a blood test that shows a reaction to M. tuberculosis. "However, these tests cannot determine which individuals with the latent form will develop active TB disease," the researchers said in a statement.

In the 400-patient study, an international team of researchers led by Mathew Berry of the MRC National Institute for Medical Research generated genome-wide transcriptional profiles of blood samples from patients with active TB before they received treatment, patients with latent TB, and healthy controls.

The researchers then constructed a 393-transcript signature in patients with active TB and applied that signature to a test set in London and a validation set in South Africa, representing intermediate and high-burden TB regions. Each cohort included 54 participants, and included patients with active TB, latent TB, and healthy controls.

Hierarchical clustering of transcriptional profiles showed that patients with active TB "cluster independently of latent TB and healthy controls" in both cohorts, the researchers reported in the paper. However, the transcriptional profiles of between 10 percent and 25 percent of patients with latent TB in both cohorts clustered with patients with active TB, suggesting that a subset of patients in the latent and active TB groups shared similar signatures.

Given this, the researchers were able to identify "a specific 86-transcript signature that discriminates active [pulmonary] TB from other inflammatory and infectious diseases." After conducting modular and pathway analysis, researchers determined that the TB signature "was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-c and type I IFN-ab signaling." After comparing the 86-transcript signature to transcriptional signatures in purified cells and flow cytometric analysis, the researchers concluded that "this TB signature reflects changes in cellular composition and altered gene expression."

Acknowledging the need for additional research in this area, the researchers characterized the findings as a "significant step towards the development of a blood test using this genetic signature to effectively predict which people with the latent form of the disease will go on to have active TB.

"This would enable thousands of people likely to progress to active TB to be diagnosed and treated earlier," they said.

The MRC-led team noted that the study also provides insight into the mechanism of TB in the human body. The research suggests that neutrophils and genes activated type I interferon "may be more important in the development of TB than previously thought," they noted. "These findings may eventually help researchers to design more effective vaccines or treatments to help the body fight TB."

In a similar but separate effort announced last week, the Institut Mérieux, BioMérieux's in vitro diagnostics arm, said it is collaborating with the Singapore government to discover biomarkers for identifying individuals who may be at risk for developing tuberculosis and to help guide drug therapies.

The partners are investing S$3 million ($2.2 million) in the project, which aims to create a joint laboratory in Singapore's R&D hub Biopolis, where researchers will study immune cells of patients with latent TB infection. These patients' cells will be compared to those with active TB and healthy controls to identify biomarkers for TB infection and reactivation.

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