Mendelian susceptibility to mycobacterial disease (MSMD) is a primary immunodeficiency syndrome characterized by severe disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy patients. Patients with MSMD are also vulnerable to tuberculosis and salmonellosis, though other infections are rare. First described clinically in the 1950s, the pathogenesis of MSMD remained unclear until 1996, when its first genetic etiology was deciphered in children with interferon- receptor 1 (IFN-R1) deficiency. Genetic dissection of MSMD over the last fifteen years has identified six morbid genes, including five autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1) and one X- linked (NEMO) gene. The high level of allelic heterogeneity at these six loci has led to the definition of up to 13 distinct disorders. The pathogenesis of MSMD in patients with these disorders involves impaired interleukin-12 (IL-12)-dependent IFN- immunity. However, only about half of the 600 patients tested in our laboratory carried any of these genetic defects. We hypothesize that MSMD in other patients results from other monogenic inborn errors of immunity, possibly but not necessarily involving the IL-12-IFN- circuit. A hypothesis-based, candidate gene approach focused on genes involved in the IL-12-IFN- circuit and related to the known MSMD-causing genes is being funded by the NIH grant 1R01AI089970. Therefore, the principal objective of the work described in this application is to identify new MSMD-causing genes by following a complementary, hypothesis-generating, genome-wide (GW) screening approach. In the present, GW approach, we will search for and characterize MSMD-causing genes by GW linkage (for both X-linked and autosomal recessive traits) and GW deep sequencing (by whole-exome sequencing). A novel method of GW linkage has been developed in the lab and whole-exome deep sequencing has been pioneered by our lab for other infectious diseases. Following this approach, we have obtained strong preliminary evidence of five novel MSMD-causing genes, with recessive mutations in X-linked CYBB and autosomal TYK2, JAK2, ISG15, and AP4E1. These five discoveries are very surprising, each in a unique way, and together they neatly illustrate the power of GW approaches and whole-exome sequencing in particular. Our project is therefore highly innovative, feasible, and supported by strong preliminary evidence. From a basic biological standpoint, this research will provide considerable and novel insights into the mechanisms of immunity to mycobacteria. Elucidation of the molecular genetic basis of MSMD will also shed light on the pathogenesis of mycobacterial disease, making it possible to provide molecular diagnoses for patients and genetic counseling for families. This new information will pave the way for the use of IFN- or other cytokines for the treatment of mycobacterial diseases, in addition to antibiotics. Finally, the genetic dissection of MSMD will pave the way for the genetic dissection of severe tuberculosis in otherwise healthy children.

Public Health Relevance

The known genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD) impair interferon (IFN)--mediated immunity. Nearly half the patients with MSMD lack a genetic etiology. We hypothesize that MSMD in these patients also results from inborn errors of immunity, which we aim to identify using hypothesis- free, GW approaches.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IMM-N (52))
Program Officer
Johnson, David R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rockefeller University
Other Domestic Higher Education
New York
United States
Zip Code
Rosain, Jérémie; Kong, Xiao-Fei; Martinez-Barricarte, Ruben et al. (2018) Mendelian susceptibility to mycobacterial disease: 2014-2018 update. Immunol Cell Biol :
Esteve-Solé, Ana; Sologuren, Ithaisa; Martínez-Saavedra, María Teresa et al. (2018) Laboratory evaluation of the IFN-? circuit for the molecular diagnosis of Mendelian susceptibility to mycobacterial disease. Crit Rev Clin Lab Sci 55:184-204
Rosain, Jérémie; Oleaga-Quintas, Carmen; Deswarte, Caroline et al. (2018) A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12R?1 Deficiency. J Clin Immunol :
Bucciol, Giorgia; Moens, Leen; Bosch, Barbara et al. (2018) Lessons learned from the study of human inborn errors of innate immunity. J Allergy Clin Immunol :
Kong, Xiao-Fei; Martinez-Barricarte, Ruben; Kennedy, James et al. (2018) Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol 19:973-985
Casanova, Jean-Laurent; Abel, Laurent (2018) Human genetics of infectious diseases: Unique insights into immunological redundancy. Semin Immunol 36:1-12
Abel, Laurent; Fellay, Jacques; Haas, David W et al. (2018) Genetics of human susceptibility to active and latent tuberculosis: present knowledge and future perspectives. Lancet Infect Dis 18:e64-e75
Louvain de Souza, Thais; de Souza Campos Fernandes, Regina C; Azevedo da Silva, Juliana et al. (2017) Microbial Disease Spectrum Linked to a Novel IL-12R?1 N-Terminal Signal Peptide Stop-Gain Homozygous Mutation with Paradoxical Receptor Cell-Surface Expression. Front Microbiol 8:616
Kagawa, Reiko; Fujiki, Ryoji; Tsumura, Miyuki et al. (2017) Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants. J Allergy Clin Immunol 140:232-241
Hatipoglu, Nevin; Güvenç, B Haluk; Deswarte, Caroline et al. (2017) Inherited IL-12R?1 Deficiency in a Child With BCG Adenitis and Oral Candidiasis: A Case Report. Pediatrics 140:

Showing the most recent 10 out of 45 publications