Research project identifying inborn errors of immunity in tuberculosis (TB) to propose new immune-system-restoring treatments for TB. Coordinated by Laurent Abel, Senior Researcher (DRCE), INSERM.
Duration of the project: 2018-2021 (currently underway)
The project aims to identify and characterize novel single-gene inborn errors of immunity responsible for childhood and adult TB. This objective will be achieved by using 1) cutting-edge genome-wide strategies, including, in particular WES (whole exome sequencing) analyses, and 2) in-depth functional studies to validate the genetic variants identified. This strategy will be applied to a unique collection of patients with either childhood or adult TB based on a large international network of collaborations.
INSERM has an important and large network of national and international collaborations established over the last 20 years and has recruited a large sample of TB patients. For childhood TB, the patients included in this project are children (<18 years old) with a life-threatening, disseminated form of TB requiring hospitalization. For adult TB, only patients > 18 years with bacteriologically confirmed pulmonary TB are included. The main sample was collected in Morocco from more than 640 pulmonary TB patients as well as from 850 TB-infected healthy controls, as assessed by positive Tuberculin skin test and Quantiferon test. INSERM has WES data for 180 pulmonary TB patients and 130 TB-infected healthy controls. In addition, they have access, for replication studies, to available DNA samples from > 2500 adult TB patients and controls of different ethnic origins from Madagascar, Mexico, Colombia, Vietnam, and Haiti. The project will:
- Identify inborn errors of immunity in tuberculosis by whole exome sequencing analyses
- Validate and functionally characterize the promising mutations
- Produce preliminary results
WES data for a unique cohort of more than 350 children with TB and more than 300 adult patients with pulmonary TB. Elucidation (identification, characterization and validation) of new molecular genetic bases of TB. Identification of the critical immunological pathways controlling the human response to Mycobacterium tuberculosis (Mtb) in natural conditions of infection.
Overall, the information gained from this project should pave the way for a novel and paradigm-shifting approach to the rational design of novel immune-system-restoring treatments of TB, fundamentally different from current vaccines and antibiotics. The basic concept is to restore a partially deficient immunity in some “predisposed’ subjects at the level of most infected individuals who are naturally resistant to developing clinical TB. The best example is provided by patients with Interleukin-12 receptor (IL-12Rβ1) and Tyrosine kinase 2 (TYK2) deficiencies. These patients, who suffer from TB due to a lack of Interferon gamma (IFN-γ) production, can be effectively treated by injections of recombinant human IFN-γ, in addition to anti-mycobacterial drugs. In this regard, the preliminary results leading to the identification of a more common TYK2 deficiency in TB patients are extremely encouraging for the development of this new kind of treatment.