On the trail of TB

Researchers find new genomic signature for TB that can predict future patients

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COLUMBUS, Ohio—Although tuberculosis (TB) is believed to have been present in the skeletal remains of Egyptian mummies in 3000 B.C., was a leading cause of death in the United States in the 20th century and still affects 10 million people worldwide, there has been no way to predict which individuals are likely catch the debilitating, deadly disease—until now.

An international study has unearthed the key to identifying future TB patients with gene expression microarray technology used to analyze blood samples and develop blood profiles specific to infectious diseases such as TB, pneumonia and bronchiolitis. This technology unlocks the first complete description of the blood transcriptional signature of TB, thus opening the door toward giving epidemiologists and healthcare clinicians a jumpstart on treating susceptible children across the globe.

Drs. Octavio Ramilo and Asuncion Mejias, investigators at the Columbus, Ohio-based Center for Vaccines and Immunity in the Research Institute at Nationwide Children's Hospital (NCH), were members of the international team that conducted the significant study, published in the Aug. 19 issue of Nature.

Researchers examined and compared blood drawn from patients in London, England, and Cape Town, South Africa, with active TB, latent TB and no TB at all, and developed genome-wide transcriptional profiles for each of the patients, discovering a distinct characteristic, or signature of the blood from patients with active TB. X-rays of patients with this signature were consistent with signs of active TB.

Mejias explains that each infectious agent, be it a virus or a bacterium, interacts with human immune cells in unique ways by triggering proteins on white blood cells, allowing researchers to identify patterns among the white blood cell's activated proteins before identifying a unique signature for each infectious agent.

Led by lead investigator Matthew P.R. Berry in the U.K., these findings "are part of a group effort by several centers—including our own—to apply this technology to improve the diagnosis of infections," Ramilo says. "Using a small blood sample, we can look at how each type of pathogen activates the body's immune system in response to the infection. By measuring the level of gene activation or suppression, we can study the response to these infections."

The study "shows for the first time that the transcriptional signature in blood correlates to the extent of disease in active TB patients, thus validating the idea that this transcriptional signature is an accurate marker of TB infection," he says. "This study establishes the proof-of-principle of the value of this approach to improve diagnosis and to assess disease activity."

Regarding the relevance of the study's findings, Berry explains that they provide a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.

"Such a comprehensive, unbiased survey will provide insights into the immunopathogenesis of TB, leading to advances in control of this complex disease," Berry says. "We show for the first time that the transcriptional signature in blood correlates with extent of disease in patients with active TB, and reflects changes at the site of disease."

The U.K. patients were of diverse ethnicity, potentially infected with different M. tuberculosis lineages, suggesting the signature may be independent of bacterial clade, although molecular typing was not available. 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, potentially identifying patients with latent TB, with subclinical active disease or higher-burden latent infection.

Further study is needed since traditional tools to diagnose infections like TB, bronchiolitis and pneumonia "are actively used to classify patients as being infected with specific pathogens, but we are still unable to predict how each person is going to react to the infection," says Romilo. "It's difficult to predict patient outcomes, and this is a real problem."

Current TB tests have limitations and "do not distinguish very well between latent, old and active infections unless you have marked radiological changes in your lungs," Ramilo adds. "Also, when we get sputum cultures, it takes several weeks to grow the TB bacilli."

However, investigators at NCH are developing transcriptional signatures using blood samples obtained from children with bronchiolitis and pneumonia and plan to correlate these findings with clinical outcomes, similar to the recent TB study, he says.

"It seems that we are developing a tool that can not only diagnose infectious diseases, but also indicate severity and eventually predict which patients are at risk for developing advanced symptoms," Ramilo says. "These capabilities are desperately needed in order to improve how patients recover from infections."

Research is a series of small steps, he notes.

"To be honest, I am not sure what the next steps will be in terms of the TB project run by our colleagues in the U.K.," he says. "Our group is more focused in common infections in children. We are applying this technology to improve the diagnosis of young babies who present to the emergency department with fever, and of children with pneumonia."

This latest study on the predictability of TB opens the door to future commercial possibilities, he says.

"As we begin to have more information in more diseases and can establish its value in large numbers of patients, there will be significant opportunities for companies interested in moving from a research tool to a practical clinical application," Ramilo says. "The timing will depend on how long it will take to demonstrate these concepts with traditional research funding mechanisms—which now are very tight." 

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