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.
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.
|Martínez-Barricarte, Rubén; Megged, Orli; Stepensky, Polina et al. (2014) Mycobacterium simiae infection in two unrelated patients with different forms of inherited IFN-?R2 deficiency. J Clin Immunol 34:904-9|
|Bustamante, Jacinta; Boisson-Dupuis, Stéphanie; Abel, Laurent et al. (2014) Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-? immunity. Semin Immunol 26:454-70|
|Conley, Mary Ellen; Casanova, Jean-Laurent (2014) Discovery of single-gene inborn errors of immunity by next generation sequencing. Curr Opin Immunol 30:17-23|
|Ouederni, Monia; Sanal, Ozden; Ikinciogullari, Aydan et al. (2014) Clinical features of Candidiasis in patients with inherited interleukin 12 receptor *1 deficiency. Clin Infect Dis 58:204-13|
|Prando, Carolina; Samarina, Arina; Bustamante, Jacinta et al. (2013) Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Medicine (Baltimore) 92:109-22|
|Kong, Xiao-Fei; Bousfiha, Aziz; Rouissi, Abdelfettah et al. (2013) A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease. PLoS One 8:e58286|
|Casanova, Jean-Laurent; Abel, Laurent (2013) The genetic theory of infectious diseases: a brief history and selected illustrations. Annu Rev Genomics Hum Genet 14:215-43|
|Ives, Megan L; Ma, Cindy S; Palendira, Umaimainthan et al. (2013) Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function. J Allergy Clin Immunol 132:400-11.e9|
|Kong, Xiao-Fei; Vogt, Guillaume; Itan, Yuval et al. (2013) Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease. Hum Mol Genet 22:769-81|
|Kilic, Sara S; Hacimustafaoglu, Mustafa; Boisson-Dupuis, Stephanie et al. (2012) A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J Pediatr 160:1055-7|
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