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Microarray Study Reveals Tuberculosis Blood Gene Signature

By Andrea Anderson

NEW YORK (GenomeWeb News) – In a paper appearing online today in Nature, an international research team reports that they have identified a gene signature linked to active tuberculosis infection and a subset of latent TB cases.

The researchers used microarray and other analyses to find a gene transcript pattern in the blood of individuals with active TB infections that's not detected in healthy individuals. A fraction of individuals with a latent or dormant form of infection with TB-causing bacteria have the same signature, they explained, fueling speculation that the signature may eventually help find those at risk of developing active TB.

"We're very excited with the results," senior author Anne O'Garra, an immunology researcher at the MRC National Institute for Medical Research in London, said during a telephone briefing with reporters this week. "We think that they're giving a handle which might be able to help in the global combat against this devastating disease."

Tuberculosis, an infectious disease caused by the bacterial species Mycobacterium tuberculosis, can lead to severe lung damage and death. But not everyone carrying the bug goes on to develop disease, O'Garra noted.

Though it's been estimated that roughly a third of individuals around the world have been exposed to or infected by M. tuberculosis, just 10 percent or so of those with latent TB infection actually develop active disease. That has researchers puzzling over the factors that cause some individuals to develop active TB, while others with the same exposures do not.

Following a visit to the Baylor Institute for Immunology Research, O'Garra said, she and her colleagues hit on the idea of using microarrays to explore TB-related gene expression patterns — a strategy that ultimately led to a collaboration between the British and American teams.

The researchers used Illumina HumanHT-12 v3 BeadChip arrays to assess gene transcript patterns in blood samples from 42 individuals recruited in London, including 13 participants with active TB, 17 with latent TB, and a dozen healthy controls.

"By doing this study in London, we were able to involve individuals from a really wide range of backgrounds and diverse ethnicity and, thus, make our findings more widely applicable to this global disease than is sometimes the case," lead author Matthew Berry told reporters. Berry, who is currently a respiratory medicine consultant with the Imperial College Healthcare NHS Trust, participated in the study as a doctoral student in O'Garra's lab.

Indeed, the team found a 393-gene signature linked to active TB infection that was independent of factors such as age, sex, or ethnicity.

They subsequently verified their findings by looking at 21 active and 21 latent TB cases and a dozen controls from the UK and a second validation set from South Africa that included 20 individuals with active TB and 31 individuals with latent TB.

"The findings made in London were generalized to a different population living in different circumstances on the opposite side of the world," co-author Robert Wilkinson, an infectious disease and immunology physician affiliated with the MRC National Institute in Medical Research, Imperial College, and the University of Cape Town, said during the press briefing.

The signature, which showed up in around 10 percent of individuals with latent infection, seemed to reflect the severity of TB disease, researchers noted, disappearing with successful TB treatment. Based on these findings, they suggested that the signature may serve as a tool for both classifying individuals with latent infections and monitoring treatment response.

"The proportion of latent patients having a transcriptional signature similar to that of active TB was equal to the expected frequency of patients at risk of progression to active disease," the team wrote, "potentially identifying patients with latent TB with sub-clinical active disease or higher burden latent infection."

The researchers' immunological studies suggest the TB-related signature reflected changes to expression of specific genes as well as alterations to levels of some cells in the blood. For instance, O'Garra said, active TB was associated with decreased levels of B-cell and T-cell lymphocytes.

Among the genes up regulated in the blood, meanwhile, were those induced by gamma interferon, a signaling pathway thought to protect against TB, and type 1 interferon, which helps combat viral infections but can aggravate some bacterial infections. Type 1 interferon-induced genes were particularly elevated in neutrophils, immune cells not previously implicated in TB infection, O'Garra noted.

"This signature that is in active TB and in 10 percent of latent [cases] is dominated by genes turned on by an immune molecule called type 1 interferon," she said. "Finding these molecules expressed in TB suggests that they may be contributing to make the disease worse."

Along with the initial signature, O'Garra explained, the team also identified another 86-gene signature that's seen in blood samples from individuals with TB but not those with other types of infections, such as those caused by Streptococcus and Staphylococcus bacteria. That signature was detected in active TB cases and in the same latent TB cases picked out by the original signature, she noted.

Those involved in the study say more research is needed to follow-up on their current findings. For instance, they plan to do additional research to explore whether the signature can, indeed, find latent TB cases at greatest risk of becoming active.

"What we have to do now is take a group of patients with latent TB, to find that blood gene signature at baseline, and follow them up over a period of time to see if they do actually develop the active disease," Berry said.

Still, the team is optimistic that their gene transcript data holds promise for improving everything from TB diagnoses and prognoses to vaccine and treatment development.

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