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The monogenic basis of human tuberculosis

Abstract

The pathogenesis of tuberculosis (TB) remains poorly understood, as no more than 5–10% of individuals infected with Mycobacterium tuberculosis go on developing clinical disease. The contribution of human genetics to TB pathogenesis has been amply documented by means of classic genetics since the turn of the twentieth century. Over the last 20 years, following-up on the study of Mendelian susceptibility to mycobacterial disease (MSMD), monogenic disorders have been found to underlie TB in some patients. Rare inborn errors of immunity, such as autosomal recessive, complete IL-12Rβ1 and TYK2 deficiencies, impairing the IL-12- and IL-23-dependent induction of IFN-γ, were initially identified in a few patients. More recently, homozygosity for a common variant of TYK2 (P1104A) that selectively disrupts cellular responses to IL-23 was found in two cohorts of TB patients. It shows high penetrance in areas endemic for TB and appears to be responsible for about 1% of TB cases in populations of European descent. Both rare and common genetic etiologies of TB affect IFN-γ immunity, providing a rationale for novel preventive and therapeutic approaches for TB control, including the use of recombinant IFN-γ.

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Acknowledgements

I thank Jean-Laurent Casanova and Laurent Abel for helpful discussions and continuous support. I also thank Gaspard Kerner, Jacinta Bustamante, Masato Ogishi, Rui Yang and Jamila El Baghdadi for great discussions and Yelena Nemirovskaya, Tatiana Kochetkov, Dominick Papandrea, Lazaro Lorenzo-Diaz, Céline Desvallées, Cécile Patissier for administrative assistance. I thank both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions. The Laboratory of Human Genetics of Infectious Diseases was supported in part by grants from the French National Agency for Research (ANR) under the “Investissement d’avenir” program (grant number ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (grant number ANR-10-LABX-62-IBEID), the TBPATHGEN project (ANR-14-CE14-0007-01), and the GENMSMD project (ANR-16-CE17-0005-01), the French Foundation for Medical Research (FRM) (EQU201903007798), the European Research Council (ERC; ERC-2010-AdG-268777), the SCOR Corporate Foundation for Science, the St. Giles Foundation, the Bill & Melinda Gates Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) of the National Institutes of Health (UL1TR001866), the National Institute of Allergy and Infectious Diseases (NIAID) (5R01AI089970, 5R37AI095983, 5U01AI088685, and 5U19AI111143), and The Rockefeller University.

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Boisson-Dupuis, S. The monogenic basis of human tuberculosis. Hum Genet (2020). https://doi.org/10.1007/s00439-020-02126-6

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