Clues to tuberculosis progression found in gene expression

Genes from a reduced published signature of TB risk are increasingly differentially expressed in incipient, subclinical, and clinical TB patients. (A) List of published TB 16-gene risk signature from Zak et al. (2016) where *** indicates the presence of a 30-gene signature from Leicester incipient, subclinical TB, and clinical TB from Table 1. (B) Volcano plots showing differential expression of the Zak 16 gene signature in blood of Leicester clinical symptoms groups compared with healthy controls (left to right: incipient TB, subclinical TB, and clinical TB; x axis represents log2 fold change of patients as compared with healthy controls; y axis represents the −log10 of adjusted P value (padj), Benjamini–Hochberg; genes with abs(log2 fold change) >1 and adjusted P value <0.05 are considered statistically significantly differentially expressed and depicted on the colored plots. Credit: DOI: 10.1084/jem.20210915

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Researchers at the Francis Crick Institute working with collaborators at the University of Leicester have identified how gene expression changes during different stages of tuberculosis (TB), including early after infection before any symptoms are clinically detectable.

These changes provided information about the host immune response which could help the development of therapies against TB. The important findings could also aid the development of tests that help doctors better assess the risk of individuals with early stages of the infection developing TB in the future and additionally monitor if treatment is proving to be successful.

Each year, around 1.5 million people worldwide die from TB, an infectious disease that affects all ages and is caused by the bacteria Mycobacterium tuberculosis. After infection, the majority of people remain healthy, with only 5% to 10% of infected people developing active TB.

Although TB is curable with appropriate medication, the treatment is toxic and can cause significant harm. Being able to reliably identify if infected individuals are at risk of developing active disease would help inform clinical decisions about whether treatment for the infection is needed. In those who have TB, measures of disease activity provided by blood gene expression changes could help support clinical decisions about how long treatment is needed.

In their study, published in the Journal of Experimental Medicine, the researchers followed a group of 356 household contacts of patients with infectious TB and followed the contacts at regular three-month intervals over the course of at least three years to determine if they developed TB.

Over the course of the study, twenty of these household contacts developed TB and the team analyzed how gene expression in their blood changed over time and during different stages of the disease. The stages of infection in these "progressors" were defined by clinical assessment and characterization as:

• Incipient TB: no symptoms, and no radiological or microbiological evidence of disease

• Sub-clinical TB: no symptoms, but either radiological or microbiological evidence of disease identified

• Clinical TB: symptoms of the disease reported and radiological or microbiological evidence of disease identified

By analyzing gene expression in serial blood samples from 14 of the progressors and linking these to the stage of disease, the scientists found that gene expression changes only minimally from health in incipient TB, with changes increasing in cases of sub-clinical TB and becoming most pronounced in clinical TB. The changes were greatest on average 30 days before diagnosis with active TB.

The researchers also analyzed gene expression in serial blood samples from patients with active TB from the start to the end of their treatment and identified differences in gene expression that correlated with response to treatment. The differences, which were present before treatment and just one week after the start of treatment, could form the basis of new biomarker tests that are more sensitive than tools currently used to assess the treatment response, offering the prospect of personalized treatment plans for patients with TB in the future.

Anne O'Garra, lead author and group leader of the Immunoregulation and Infection Laboratory at the Crick says: "There are significant differences in gene expression in the blood as TB progresses and throughout treatment. These differences could be used to help develop biomarkers, which doctors could use as a means to see what stage of disease an individual has reached, as well as to predict if, and how soon, the disease may become active in individuals with incipient or sub-clinical TB. This would be really valuable as it could help with key decisions such as when to start treatment.

To my knowledge, this study is the first to relate clinical parameters during TB progression with temporal blood gene expression changes, providing a knowledge of the immune response at an early stage after infection which may explain why certain individuals progress to disease and help to direct future potential therapies.

Of the individuals who became infected and developed the active disease, in the majority of cases, this happened in the first or second year after infection. This suggests that in some reported cases where it seems that latent TB has progressed to active TB after many years, the disease may in fact have been the result of the individual being exposed to and re-infected with the bacteria, as is common in countries where the burden of TB is very high.

Co-lead author, Dr. Pranab Haldar, at Leicester University said, the results of this study are very encouraging as they indicate that immune response markers exist which can provide a reliable and sensitive measure of how active the infection is. This in turn can tell us about an individual's risk of developing TB; and if they have TB, the trajectory of their response to treatment. Through this work, immune response markers could support a personalized approach to management across the spectrum of Mycobacterium tuberculosis infection in the future.

The researchers will continue this work, carrying out further analysis of the airway response in TB household contacts that remain healthy or progress to active TB after infection, with the aim of identifying additional mechanisms of TB outcome and targets for therapeutic intervention.

Journal Information: Olivier Tabone et al, Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis, Journal of Experimental Medicine (2021). DOI: 10.1084/jem.20210915