Human genetics and immunological determinants of tuberculosis.
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). Despite its major global health burden, the mechanisms underlying susceptibility to TB remain incompletely understood. Approximately one-quarter of the world's population is infected with Mtb, yet only 5–10% of infected individuals develop active disease, while the majority remain asymptomatic throughout life.
Fifteen years ago, we proposed that TB could, at least in some individuals, be a genetic disease. Since then, we have demonstrated that TB can result from monogenic inborn errors of immunity (IEIs). Our work has identified two forms of genetic predisposition:

Rare pathogenic variants that account for susceptibility in a small proportion of patients
Common genetic variants acting in a recessive manner, such as homozygosity for the TYK2 P1104A variant, which accounts for approximately 1% of TB cases in populations of European descent

The study of these genetic defects has revealed critical pathways involved in protective immunity against Mtb, highlighting the essential roles of the cytokines IFN-γ, IL-12, IL-23, and TNF.
We hypothesize that TB may arise from a diverse collection of rare and common single-gene inborn errors of immunity that impair host defense against Mtb.
To investigate this hypothesis, we recruit patients with TB and conduct comprehensive genome-wide analyses to identify both rare and common IEIs associated with disease susceptibility. Using state-of-the-art next-generation sequencing (NGS) approaches, we aim to uncover the genetic basis of susceptibility to TB and define the causal impact of genetic variants on human immunity to Mtb.
Ultimately, this work seeks to improve our understanding of the mechanisms of protective immunity against TB and pave the way toward more precise diagnostic and therapeutic strategies.
Key references
Human LY9 governs CD4+ T cell IFN-γ immunity to Mycobacterium tuberculosis.
Ogishi M, Puchan J, Yang R, Arias AA, Han JE, Nguyen T, Gutiérrez-Cózar R, Conil C, Seeleuthner Y, Rinchai D, Zhang P, Ponsin K, Chaldebas M, Feng Y, Neehus AL, Delmonte OM, Khan T, Landegren N, Eriksson D, Bohlen J, Peel JN, Fagniez I, Pelham SJ, Lei WT, Chrabieh M, Laine C, Ouair H, Benhsaien I, Abid A, Abderrhamani Ghorfi I, Souhi H, Ouazzani H, Aniss R, Riminton DS, Kämpe O, Turvey SE, Marr N, Notarangelo LD, Hatipoglu N, Bousfiha A, Ozcelik T, El Baghdadi J, Cobat A, Ma CS, Abel L, Puel A, Bustamante J, Engel P, Gros P, Tangye SG, Sallusto F, Boisson-Dupuis S, Casanova JL.Sci Immunol. 2025 May 30;10(107):eads7377. doi: 10.1126/sciimmunol.ads7377. Epub 2025 May 30.PMID: 40446017
 
Tuberculosis in otherwise healthy adults with inherited TNF deficiency.
Arias AA, Neehus AL, Ogishi M, Meynier V, Krebs A, Lazarov T, Lee AM, Arango-Franco CA, Yang R, Orrego J, Corcini Berndt M, Rojas J, Li H, Rinchai D, Erazo-Borrás L, Han JE, Pillay B, Ponsin K, Chaldebas M, Philippot Q, Bohlen J, Rosain J, Le Voyer T, Janotte T, Amarajeeva K, Soudée C, Brollo M, Wiegmann K, Marquant Q, Seeleuthner Y, Lee D, Lainé C, Kloos D, Bailey R, Bastard P, Keating N, Rapaport F, Khan T, Moncada-Vélez M, Carmona MC, Obando C, Alvarez J, Cataño JC, Martínez-Rosado LL, Sanchez JP, Tejada-Giraldo M, L'Honneur AS, Agudelo ML, Perez-Zapata LJ, Arboleda DM, Alzate JF, Cabarcas F, Zuluaga A, Pelham SJ, Ensser A, Schmidt M, Velásquez-Lopera MM, Jouanguy E, Puel A, Krönke M, Ghirardello S, Borghesi A, Pahari S, Boisson B, Pittaluga S, Ma CS, Emile JF, Notarangelo LD, Tangye SG, Marr N, Lachmann N, Salvator H, Schlesinger LS, Zhang P, Glickman MS, Nathan CF, Geissmann F, Abel L, Franco JL, Bustamante J, Casanova JL, Boisson-Dupuis S.Nature. 2024 Sep;633(8029):417-425. doi: 10.1038/s41586-024-07866-3. Epub 2024 Aug 28.PMID: 39198650
 
Inborn errors of human transcription factors governing IFN-γ antimycobacterial immunity.
Ogishi M, Yang R, Rosain J, Bustamante J, Casanova JL, Boisson-Dupuis S.Curr Opin Immunol. 2023 Apr;81:102296. doi: 10.1016/j.coi.2023.102296. Epub 2023 Mar 1.PMID: 36867972 Review.
 
Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis.
Ogishi M, Yang R, Rodriguez R, Golec DP, Martin E, Philippot Q, Bohlen J, Pelham SJ, Arias AA, Khan T, Ata M, Al Ali F, Rozenberg F, Kong XF, Chrabieh M, Laine C, Lei WT, Han JE, Seeleuthner Y, Kaul Z, Jouanguy E, Béziat V, Youssefian L, Vahidnezhad H, Rao VK, Neven B, Fieschi C, Mansouri D, Shahrooei M, Pekcan S, Alkan G, Emiroğlu M, Tokgöz H, Uitto J, Hauck F, Bustamante J, Abel L, Keles S, Parvaneh N, Marr N, Schwartzberg PL, Latour S, Casanova JL, Boisson-Dupuis S.J Exp Med. 2023 Jan 2;220(1):e20220484. doi: 10.1084/jem.20220484. Epub 2022 Nov 3.PMID: 36326697
 
The monogenic basis of human tuberculosis.
Boisson-Dupuis S.Hum Genet. 2020 Jun;139(6-7):1001-1009. doi: 10.1007/s00439-020-02126-6. Epub 2020 Feb 13.PMID: 32055999 . Review.
 
Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant.
Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G, Kerner G, Lim CK, Krementsov DN, Hernandez N, Ma CS, Zhang Q, Markle J, Martinez-Barricarte R, Payne K, Fisch R, Deswarte C, Halpern J, Bouaziz M, Mulwa J, Sivanesan D, Lazarov T, Naves R, Garcia P, Itan Y, Boisson B, Checchi A, Jabot-Hanin F, Cobat A, Guennoun A, Jackson CC, Pekcan S, Caliskaner Z, Inostroza J, Costa-Carvalho BT, de Albuquerque JAT, Garcia-Ortiz H, Orozco L, Ozcelik T, Abid A, Rhorfi IA, Souhi H, Amrani HN, Zegmout A, Geissmann F, Michnick SW, Muller-Fleckenstein I, Fleckenstein B, Puel A, Ciancanelli MJ, Marr N, Abolhassani H, Balcells ME, Condino-Neto A, Strickler A, Abarca K, Teuscher C, Ochs HD, Reisli I, Sayar EH, El-Baghdadi J, Bustamante J, Hammarström L, Tangye SG, Pellegrini S, Quintana-Murci L, Abel L, Casanova JL.Sci Immunol. 2018 Dec 21;3(30):eaau8714. doi: 10.1126/sciimmunol.aau8714.PMID: 30578352