Deciphering tuberculosis pathogenesis by identifying single-gene inborn errors of immunity in severe childhood forms of the disease – TBPATHGEN

Tuberculosis (TB) remains a major public health problem. One fundamental although often neglected observation is that only a minority of individuals infected with Mycobacterium tuberculosis (Mtb) develop clinical TB. This phenomenon is largely unexplained, and the pathogenesis of TB therefore remains unclear. TB development may be triggered by acquired immunodeficiency, such as HIV infection or anti-TNF-a treatment. In other patients, TB may be the result of inborn errors of immunity and qualified as a bona fide genetic disorder. A century of surveys in genetic epidemiology, half a century of studies in mouse models of TB, and a decade of investigations in human molecular genetics have provided firm foundations for studies of TB pathogenesis through the lens of human genetics. With the advent of next-generation sequencing (NGS), the in-depth genetic dissection of TB is timely and this approach lies at the crossroads of multiple disciplines. Here, we aim to decipher human immunity to TB, by identifying single-gene inborn errors of immunity underlying severe childhood TB. Our previous discoveries of IL12RB1 and TYK2 mutations in severe TB, in particular thanks to a previous ANR support, provide a strong rationale for this project. More recently, we have identified other candidate mutations of IL12RB2, NCF2, STAT1, and ICAM3, for which functional investigations are underway. In the present project, we intend to investigate 200 children with severe TB by a genome-wide approach combining 1) NGS and population genetics analyses to identify promising variants using a cutting-edge strategy we have developed, and 2) in-depth functional studies to validate those variants taking advantage of the extensive expertise we have acquired in characterizing single-gene inborn errors of immunity since 20 years. Our project is groundbreaking, as childhood TB is not generally thought to be a genetic disorder. However, it is achievable, as it builds on strong preliminary data, and presents with several major strengths: 1) the integrated approach to the human molecular genetic basis of severe TB in children, 2) the high quality of the clinical samples from our long-standing field collaborators, 3) the extensive, multi-disciplinary experience of our consortium in the human genetics of mycobacterial infections in terms of genetic epidemiology, population genetics, clinical genetics, molecular genetics, and cellular immunology, 4) the use of cutting-edge NGS approaches, which we have successfully pioneered in the field of immunology and infectious diseases. The genetic dissection of TB will revolutionize our understanding of the pathogenesis of TB. The identification of the main variants controlling the development of disseminated TB in childhood is fundamental to an understanding of the human immune response to Mtb and to the definition of biological markers for recognizing infected individuals prone to the development of clinical TB. The clinical implications of these findings are also considerable, in terms of diagnosis, prognosis and treatment. Molecular genetic diagnosis and genetic counseling will be offered to the study subjects and their families. In addition, new avenues of treatment, aiming to restore immunity to Mtb, will be devised on the basis of knowledge about the inborn errors of immunity conferring predisposition to TB. As an example, TB patients with impaired IFN-gamma production (as those with IL-12Rß1 and TYK2 deficiencies) could be treated by recombinant human IFN-gamma, in addition to antimycobacterial drugs.