Approved research

Search for candidate gene variants predisposing to tuberculosis

Lay summary

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). TB remains one major public health problem as more than nine million individuals worldwide develop TB each year, and an estimated one third of the world population is infected with Mtb. However, most infected subjects remain asymptomatic, and only ~5-10% of them will develop clinical TB within their lifetime. What accounts for the natural resistance of most infected individuals, and the predisposition to TB of only a few? This is the most fundamental question in the field of TB, and despite 50 years of research into the mechanisms of protective immunity to Mtb, it remains unanswered. Proof-of-principle was recently obtained that human genetic variability may account at least in part for this clinical variability upon infection with Mtb. In particular, we recently showed that some rare monogenic disorders highly predisposed to TB. These genetic disorders affect an immune circuit involving a cytokine denoted as Interferon (IFN)-gamma. Mutations are found in several genes leading to an impairment of the production of or the response to IFN-gamma. All these mutations are very rare, and explain a very small proportion of TB cases. The general objective of this project is to search for the role of more common genetic variants in TB within candidate genes, taking advantage of the UK biobank database including 654 patients with TB. These candidate genes include mainly those of the IFN-gamma circuit, in particular those for which rare mutations are known to cause TB. Association between variants of these genes will be tested between the TB patients and the subjects without any history of TB of the database. The identification of molecules and pathways crucial for anti-TB immunity are essential for the development of efficient vaccines and treatments based on physiopathology. In particular it will pave the way for treatments aimed at restoring a partially deficient immunity which are of major interest to complement classical antibiotic treatments in the present context of increasing number of drug resistant Mtb strains. The best example of these treatments is provided by patients who suffer from TB because of mutations in genes affecting the production of IFN-gamma (eg the gene IL12RB1 encoding the receptor of Interleukin-12), and can be effectively treated by injections of recombinant human IFN-gamma in addition to anti-mycobacterial drugs.