Francis Crick Institute news release
A gene signature in the bloodstream could reveal whether someone is going to develop active tuberculosis (TB) disease months before symptoms begin. Such a signature has now been developed by a team led by the Francis Crick Institute and University of Leicester, in collaboration with BIOASTER and bioMérieux in France and the University of Cape Town in South Africa.
The research, published in Nature Communications, looked at 53 TB patients in Leicester and followed 108 of their close contacts over two years to see who developed active TB. They found that those who remained healthy showed no sustained gene signature, while six of the nine who went on to develop active TB showed a strong, sustained signature.
This is the first study to link the presence of signature and the onset of early TB before the patient has symptoms. This small proof-of-principle study shows a promising new direction for TB detection and treatment, also with the prospect of intervening before individuals pose a risk of transmitting the infection to others.
Two billion people worldwide have been estimated to have been infected by the bacterium that causes TB, but only 10% of them develop clinically active disease, which kills 1.67 million people every year. The other 90% have ‘latent’ TB, where the immune system keeps the infection under control and they do not experience symptoms or spread the disease. Knowing who is likely to develop active TB would help doctors to better prevent and treat the disease before symptoms begin.
Symptoms of active TB include persistent cough, followed by weight loss, fever and breathing difficulties. TB can be fatal if left untreated, and even when treated promptly the symptoms can last for several weeks during which time the patient remains infectious.
“Treating active TB before symptoms start could spare patients and their families from unpleasant symptoms, reduce the spread of disease and offer peace of mind to people who are not going to develop active TB,” explains Professor Anne O’Garra, Group Leader at the Francis Crick Institute, senior author of the paper. “This study was a promising proof-of-principle, offering new insights into how to develop gene signatures for active TB. The next step will be to develop and test different gene signatures in larger groups of people, with the aim of being able to offer validated tests to patients within the next decade.”
The team previously identified the full blood gene signature for active TB, and various groups around the world have since reproduced this signature and tried to narrow it down to a handful of genes that could be used in a field test.
The gene ‘signature’ refers to the genes that are either more or less active during active TB, representing the body’s response to the infection. Previous approaches to find the key genes used algorithms to highlight the genes whose activity changed the most during active TB. However, some of the genes that are most active during TB are also active in other infections such as viral infections.
In the latest study, the team first analysed blood samples from patients across London and Africa with latent and active TB. They used global gene signatures from these patients to develop, in collaboration with BIOASTER, a panel of 20 key genes, combining computational methods with their understanding of the immune response to exclude genes that signal a more general response to infection. They tested this alongside other gene sets in data from both TB patients and those with viral infections including flu.
The results showed that other gene signatures, developed by other groups using standard methods, inadvertently detected viral infection since they included more general immune response genes. However, this new study now shows that the new 20-gene signature did not detect viral infections.
“We all know that any viral infections can make us feel unwell for a couple of weeks,” says Anne. “This is likely due to our lingering immune response, which is what blood gene signatures will pick up.”
This 20-gene signature was then tested at the Crick in contacts of TB patients in Leicester, recruited by co-author Dr Pranab Haldar’s team at the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, a partnership between Leicester’s Hospitals and the University of Leicester. The signature was not sustained in contacts who remained healthy, while six of the nine who went on to develop active TB showed a strong, sustained signature.
“Being able to track TB patients’ contacts and take monthly blood samples gave us a unique insight into how immune responses develop,” explains Dr Haldar, Senior Clinical Lecturer in Respiratory Medicine at the University of Leicester. “There was a wide variation in the immune response between people, highlighting the limitations of taking a ‘one size fits all’ approach. The next step will be to better understand what the different responses mean and we will need to study larger groups in detail to achieve this. The ability of our signature to distinguish from viral infections is an important step forward for developing reliable tests that we can use in the clinic. In the contacts we saw, the new 20-gene signature performed better than previous signatures but there is still work to be done. We only saw a small number of contacts who developed TB in the group, so we will need to look at much larger groups to refine and develop the techniques.”
Nathalie Garçon, PharmD, PhD, CEO/CSO of BIOASTER concludes: “As a leader in public-private partnerships, BIOASTER provided its technologies and know-how to facilitate collaboration with world renowned public and private partners. In this project, BIOASTER, through data analysis and integration, contributed to identify key biomarkers for the diagnostic of TB. This is perfectly in line with our mission to speed up the process from academic research to product development and, thus, to deliver the innovation sooner to the patients.”
“bioMérieux is a proud collaborator in this important project in order to develop diagnostic tests of high medical value, especially for important global diseases like tuberculosis,” states Mark Miller, Executive Vice President, Chief Medical Officer of bioMérieux. “In this multidisciplinary team effort, we hope to address the unmet medical need of diagnosing active tuberculosis earlier, more easily and more reliably.”
Notes to Editors
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Contributors to the study to be published in Nature Communications are from:
The Francis Crick Institute
The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases. An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London. The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe. http://crick.ac.uk/
bioMérieux is a world leader in the field of in vitro diagnostics for more than 55 years. The Company is committed to serving public health through the development of high medical value solutions for the diagnosis of infectious diseases.
Created in April 2012 by Pasteur Institute and Lyonbiopôle health competitiveness cluster, following the initiative of the French government, BIOASTER Technological Research Institute (TRI) is working to develop an unique technological and innovative model to support the latest challenges in microbiology, in particular to fight antimicrobials resistance, improve vaccines safety and efficacy, quickly diagnose infections at patient bedside and take full advantage of human and animal microbiota.
In order to overcome technological bottlenecks and explore new avenues, BIOASTER is leading collaborative projects that bring together academics, start-ups, SMEs and industrial groups that rely on the support of the French Government through the "Investissements d'Avenir", infrastructures funded by regional authorities (Lyon Metropolis and the Auvergne-Rhône-Alpes Region), world-class academics and industries (the Pasteur Institute, CEA, CNRS, Inserm, Danone Nutricia Research, Institut Mérieux and Sanofi Pasteur) and from highly dynamic SMEs and regional cluster.
With more than 120 collaborators, coming equally from industries & academics, of which the large majority are scientists and engineers originating from 18 different citizenships, BIOASTER drive new technologies innovation in its own infrastructures with state of the art equipment.
The aim of BIOASTER is to:
The NIHR Leicester Biomedical Research Centre
The National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) is a partnership between University Hospitals of Leicester NHS Trust, the University of Leicester and Loughborough University. It is funded by the National Institute for Health Research (NIHR).
The NIHR Leicester BRC undertakes translational clinical research in priority areas of high disease burden and clinical need. These include cardiovascular disease, respiratory disease, and lifestyle, obesity and physical activity. There is also a cross-cutting theme for precision medicine. The BRC harnesses the power of experimental science to explore and develop ways to help prevent and treat chronic disease. It brings together 70 highly skilled researchers, 30 of which are at the forefront of clinical services delivery. By having scientists working closely with clinicians, the BRC can deliver research that is relevant to patients and the professionals who treat them. www.leicesterbrc.nihr.ac.uk
The National Institute for Health Research (NIHR): improving the health and wealth of the nation through research,
Established by the Department of Health and Social Care, the NIHR:
For further information, visit the NIHR website (www.nihr.ac.uk)
The Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town
The Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) at the University of Cape Town fosters investigator-led approaches via the overarching scientific objective of combatting infection, especially HIV-1 and tuberculosis, through clinical and laboratory research. CIDRI-Africa was established at the University of Cape Town to augment acknowledged strengths in the basic and clinical aspects of infectious diseases research in the Faculty of Health Sciences. In the future, CIDRI-Africa will expand its portfolio to include support for research on the interaction between communicable and non-communicable diseases, especially where the latter impact susceptibility to infection, or arise as a consequence of infection. In addition, CIDRI-Africa will improve understanding and management of the challenges of antiretroviral therapy (ART) such as metabolic complications and antiretroviral drug resistance.