Laboratory of Human Genetics of Infectious Diseases University Paris Descartes/Inserm U980 Necker medical school, 156 rue de vaugirard, 75015 Paris Email: Laurent.firstname.lastname@example.org www.hgid.net Research area of the Unit Our laboratory aims to identify the human genes involved in the response to an infectious agent. The two teams (L. Abel and J.L. Casanova) work together to address the question of genetic susceptibility to rare and common infections, from the perspective of both Mendelian and complex predisposition. In the last years, the laboratory has focused on the human genetics of specific bacterial, viral, and fungal infections. Our principal results include the identification of 1) mutations causing the syndrome of Mendelian susceptibility to mycobacterial diseases; 2) the first cases of Mendelian tuberculosis; 3) the first major loci conferring predisposition to pulmonary tuberculosis and controlling infection byM. tuberculosis; 4) major leprosy susceptibility variants; 5) a new group of primary immunodeficiencies causing invasive pneumococcal infections; 6) mutations in the TLR3 pathway causing herpes simplex encephalitis; 7) mutations impairing IL-17 T cell immunity responsible of Chronic mucocutaneous candidiasis. Contribution to the programme The contribution of the HGID laboratory to the present programme will be in the understanding of the human response to emerging infectious agents through human genetics studies (WP3). In the wake of the expansion of genomic technologies, human genetics approaches appear to be the most efficient way to identify the molecules and pathways really critical for immunity in natural conditions of infection. These studies will combine Mendelian approaches searching for rare mutations with large effect sizes (in particular, using deep-sequencing techniques) that may account for susceptibility to the most severe clinical forms (e.g. in life-threatening dengue or flu), and population genetics approaches (in particular genome-wide association studies) searching for polymorphisms that could be involved in more common phenotypes (e.g. in dengue or HCV infection). Mendelian mutations will be functionally validated and characterized by ex vivo and in vitrohuman studies in order to decipher the mechanisms underlying the disease while the biological validation of polymorphisms could be more challenging. References over the past 5 years 1. Alcaïs A, Alter A, Antoni G, …//…, Mehra N, Schurr E, Abel L. Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nat. Genet. 2007;39:517–522. 2. Zhang S-Y, Jouanguy E, Ugolini S, …//…, Tardieu M, Abel L, Casanova J-L. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522–1527. 3. von Bernuth H, Picard C, Jin Z, …//…, Abel L, Li X, Chaussabel D, Puel A, Casanova J-L. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321:691–696. 4. Cobat A, Gallant CJ, Simkin L, …//…, Casanova J-L, Abel L, Hoal EG, Schurr E, Alcaïs A. Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J. Exp. Med. 2009;206:2583–2591. 5. Pérez de Diego R, Sancho-Shimizu V, …//…, Zhang S-Y, Abel L, Casanova J-L. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity. 2010;33:400–411. 6. Bustamante J, Arias AA, Vogt G, …//…, Dinauer MC, Abel L, Casanova J-L. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat. Immunol. 2011;12:213–221. 7. Puel A, Cypowyj S, Bustamante J, …//…, Abel L, Picard C, Casanova J-L. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011;332:65–68.
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