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Tuberculosis is a common infectious disease caused by a mycobacterium called Mycobacterium tuberculosis. Around 10 million people worldwide develop tuberculosis every year, in all countries and all age groups. Nearly 1.5 million people die from the disease every year, even though it is treatable. However, treatment remains cumbersome, and bacterial strains are increasingly resistant to current antibiotics. The BCG vaccine, administered to infants as a preventive measure, is protective against meningeal tuberculosis in very young children, but offers little or no protection against the contaminating form, pulmonary tuberculosis, in adults. This disease is therefore a global public health problem.
Dr Andrés Arias and Dr Anna-Lena Neehus, under the supervision of Dr Laurent Abel, Dr Jacinta Bustamante, Pr José Franco Restrepo, Pr Jean-Laurent Casanova and Dr Stéphanie Boisson-Dupuis have identified a novel genetic cause of tuberculosis. These results are published in the prestigious scientific journal Nature. During this international collaborative study led by Dr Boisson-Dupuis, researchers followed two adult patients from the same Colombian family suffering from recurrent pulmonary tuberculosis.
Genetic analysis of these patients revealed a mutation inactivating the TNF gene. This gene encodes the protein of the same name, involved in the inflammatory response. Surprisingly, the medical follow-up of these two patients demonstrates in vivo in humans that TNF is indispensable for the immune response to tuberculosis, and appears to be redundant for other infections. The team's work focused on the role of TNF specifically in macrophages, the immune cells present in the pulmonary alveoli which are capable of internalizing and digesting microbes. TNF deficiency prevents the oxidative explosion, i.e. the rapid release of reactive oxygen species (ROS), free radicals produced by the cell to eliminate pathogens internalized by macrophages.
The importance of TNF for the production of these ROS, and thus for the immune response, has been demonstrated in the lab in several cellular models: macrophages matured with the growth factor GM-CSF (notably alveolar macrophages), derived from patients' own cells or from pluripotent iPSc cells, and “normal” lung macrophages treated with anti-TNF antibodies. However, TNF is surprisingly redundant, especially for ROS production in other phagocyte types, such as neutrophils and macrophages matured with M-CSF, which explains the limited clinical phenotype of the patients. These data also help to understand the vulnerability of patients treated with anti-TNF therapies.
Understanding the mechanisms of immune defense against tuberculosis is a major step forward in the development of curative or preventive treatments for this endemic disease. This work has confirmed that TNF activity is particularly essential in the lungs. Therefore certain types of treatment, in the form of aerosols, could be envisaged to deliver directly to the lungs the medication needed to protect, or at least relieve, those more susceptible to this bacterium and to severe forms of the disease.
Reference : Tuberculosis in otherwise healthy adults with inherited TNF deficiency, Arias et al., Nature, 2024
DOI : 10.1038/s41586-024-07866-3
Contact :
Dr Stéphanie Boisson-Dupuis, DR2 Inserm, Université Paris Cité, Inserm U1163 Institut Imagine, Université Rockefeller
Dr Jacinta Bustamante, MCU-PH, Université Paris Cité, Theme leader- Inserm U1163 Institut Imagine, Centre d’Etudes de Déficits Immunitaires, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP)
Pr Jean-Laurent Casanova, PU-PH, Université Paris Cité et Université Rockefeller, Inserm U1163 Institut Imagine, Hôpital Necker Enfants Malades, AP-HP, co-fondateur du Laboratoire de Génétique Humaine des Maladies Infectieuses