Genetic dissection of chronic muco-cutaneous candidiasis in humans – GENCMCD

With the very recent development of new strategies for genetics and genomics, it is now possible to identify relatively quickly and at low costs mutations in the coding regions of the genome or in the entire genome of individuals sequenced. By bioinformatics analyses and complementary experimental strategies, it is now feasible to easily identify mutated genes responsible for a disease.

In 2011, our identification of the first 3 genetic etiologies of chronic mucocutaneous candidiasis showed a major role of interleukin (IL)-17 in protective immunity against mucocutaneous Candida albicans infections, in natural conditions. These studies have important biological and medical implications with the possible development of therapeutic strategies based on the understanding of the physio-pathological mechanisms.

The discovery of the first genetic and immunological bases of «idiopathic« chronic mucocutaneous candidiasis with an impaired IL-17-dependent immunity highlighted the patho-physiology of candidiasis in all medical fields (HIV infection, immunosuppression, etc..). The identified mechanisms may be the target for the development of treatments (ie IL-17).

Identification of the first three genetic etiologies of «idiopathic« chronic mucocutaneous candidiasis in human associated with a specific defect of IL-17-dependent immunity: Puel et al. Science 2011; Liu et al. J Exp Med 2011; Toth et al. Lancet 2012.
Reviews of the litterature on this topic: Boisson-Dupuis et al. Curr Opin Immunol 2012 ; Cypowyj et al. Eur J Immunol 2012 ; Puel et al. Curr Opin Allergy Clin Immunol 2012.

Fungal diseases are increasingly recognized as an important public health problem. There is therefore a need to understand the molecular and cellular mechanisms involved in antifungal immunity, for timely elucidation of the pathogenesis of fungal infections in humans. This project addresses these issues, through determination of the genetic and immunological basis of chronic mucocutaneous candidiasis (CMC). CMC is characterized by severe, persistent and/or recurrent infections of the skin, nails and mucosal surfaces with fungi of the genus Candida, mostly C. albicans. CMC is commonly associated with other infections, in a context of acquired immunodeficiency, such as HIV infection or primary immunodeficiencies affecting T lymphocytes, in particular. CMC is associated with staphylococcal infections in autosomal dominant hyper IgE syndrome. CMC also occurs as the only known infection associated with an autoimmune/endocrine clinical disorder, in the autosomal recessive APECED syndrome. Finally, CMC may occur as the only clinical phenotype, with no other overt infectious or autoimmune manifestation, in which case it is known as CMCD (‘CMC disease’). Most of the reported cases of CMCD are sporadic, but familial cases with an autosomal dominant (AD) or recessive (AR) mode of inheritance have also been reported, with no genetic etiology published, yet. The aim of this project is to identify and characterize the first genetic etiologies of CMCD, with a view to defining the molecular and cellular immunological mechanisms underlying protection against C. albicans in the mucosae and skin. We will use a combination of two strategies. The first approach, the “candidate” approach, is based on hypotheses generated by our recent findings or published data on IL-17 mediated immunity. This approach involves (i) carrying out functional tests on cells from patients and (ii) directly sequencing candidate genes (identified on the basis of the cellular phenotypes studied in parallel). The second approach is a “genome-wide” approach that does not depend on the prior formulation of an immunological hypothesis and explores the whole genome through (i) positional cloning by genome-wide linkage analysis of multiplex and/or consanguineous families and (ii) direct sequencing of all the coding regions of the genome (exome), to identify unpredicted morbid genes involved in anti-fungal immunity. In our recent studies, demonstrating the feasibility and efficacy of our strategy, we identified the first two genetic etiologies of CMCD: autosomal recessive IL-17 receptor (IL-17RA) deficiency and autosomal dominant IL-17F deficiency. The power of our approach lies in the international recruitment of well characterized CMCD patients, an original working hypothesis and our considerable expertise in the use of powerful genetic and immunological tools. From a biological standpoint, the identification of genes conferring a predisposition to CMCD will have a major impact, with dissection of the mechanisms underlying the cutaneous and mucosal immune response to C. albicans and elucidation of the molecular basis of the pathogenesis of CMCD. From an immunological standpoint, this project will provide major insights into the role of IL-17 mediated immunity in humans. From a clinical standpoint, this work will provide molecular diagnoses for the patients and the possibility of genetic counseling for the families, potentially paving the way for new preventive or curative therapeutic interventions.