Description du projet
Chronic mucocutaneous candidiasis (CMC) is a rare condition characterized by persistent and recurrent infections of the skin, nails and mucous membranes. The symptoms are clinically heterogeneous and respond poorly to antifungal and other treatments. They are not themselves life-threatening, but they impair considerably the patient’s quality of life. The disease is caused by Candida albicans, an opportunistic pathogen that lives as commensal in healthy individuals and only causes disease when host defences are breached. CMC is often associated with acquired or inherited immunodeficiencies. Only lately the first genetic aetiologies of this rare disease have been described, which have brought new insights into immunological mechanisms active against candidiasis, most importantly interleukin-17-mediated mechanisms.
Initially we will use a mouse model of oral candidiasis, which is very suitable for the study of human CMC, to investigate host-protective mechanisms. The primary focus will be put on the role and regulation of interleukin-17. The findings from these experiments shall be confirmed using blood and tissue samples from CMC patients. This dual approach will enable us to rapidly confirm the relevance of newly acquired basic knowledge for the clinical diagnosis and treatment of CMC.
Complementary to the need for a detailed knowledge of antifungal immune mechanisms, a better knowledge of the variable pathogenicity of C. albicans is indispensable for an integrated understanding of the disease. The genetic traits of different clinical isolates may have a strong impact on their pathogenicity and on the consequence for the host, namely colonization versus invasion and disease. A systematic analysis of C. albicans strains isolated from CMC patients will help to establish a correlation between the genetic traits of the pathogen and the patient’s predisposition.
Together, this project shall help a better understanding of the molecular pathogenesis of CMC with the aim to identify novel therapeutic targets and diagnostic markers, and to promote the development of novel antifungal strategies.
Quelles sont les particularités de ce projet?
C. albicans is a feared pathogen that can cause severe, often fatal infections in immunocompromised people. The mechanisms allowing disease symptoms to occur remain not well understood. The support by the Gebert Rüf Stiftung allows us to pursue an integral and interdisciplinary approach to identify new host- and pathogen-derived factors that contribute to the development and control of a very rare but severe infectious disease. These efforts shall lead to the identification of novel diagnostic markers and possible therapeutic targets.
In this project we have clarified the regulation of IL-17 immunity, which is key for host protection from the opportunistic fungal pathogen C. albicans. Multiple different cell types contribute to the overall production of IL-17 in response to the fungus, which are under the control of a complex network of dendritic cells. We have further shown that IL-17 acts by instructing the production of antimicrobial effector molecules in the mucosal epithelium, rather than by recruiting neutrophil granulocytes as was previously postulated. This result has led to the identification of possible therapeutically exploitable antifungal factors, one of which is now being tested in a pre-clinical model.
In parallel, by examining the impact of natural variations in C. albicans on the interaction of the fungus with the host, we identified fungal factors that contribute to the decision between innocuous fungal colonization and symptomatic disease in susceptible hosts. The potential use of these factors as diagnostic markers or therapeutic targets will be investigated in future studies. In this project, which involved a large panel of C. albicans strains from healthy and diseased individuals, including CMC patients, we uncovered large differences in pathogenicity of strains and linked to this differences in their capacity to cause disease. However, the impact of the fungal diversity was outweighed by the requirement of a functional IL-17 pathway in the host for preventing uncontrolled fungal growth, thereby underlining the critical role of il-17 immunity in antifungal defense.
Gladiator and Leibundgut-Landmann. 2013. Innate lymphoid cells: new players in IL-17-mediated antifungal immunity. PLoS Pathogens, 9(12):e1003763. doi: 10.1371/journal.ppat.1003763;
Gladiator et al. 2013. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol., 190: 521-525. doi: 10.4049/jimmunol.120292;
Trautwein-Weidner K*, Gladiator A*, Nur S, Diethelm P, Leibundgut-Landmann S. 2014. IL-17-mediated antifungal defense in the oral mucosa is independent of neutrophils. Mucosal Immunology, 8(2):221-31. doi: 10.1038/mi.2014.57 [* equal contribution];
Trautwein-Weidner K*, Gladiator A*, Kirchner FR, Becattini S, Rülicke T, Sallusto F and Leibundgut- Landmann S. 2015. Antigen-specific Th17 cells are primed by distinct and complementary dendritic cell subsets in oropharyngeal candidiasis. PLoS Pathogens, 11(10):e1005164. doi: 10.1371/journal.ppat.1005164 [* equal contribution];
Schönherr FA, Sparber F, Kirchner FR, Guiducci E, Trautwein-Weidner K, Gladiator A, Sertou N, Hetzel U, Le GTT, Pavelka N, d’Enfert C, Bougnoux ME, Fragoso Corti C, LeibundGut-Landmann S. 2017. The intraspecies diversity of C. albicans triggers qualitatively and temporally distinct host responses that determine the balance between commensalism and pathogenicity. Mucosal Immunology. doi:10.1038/mi.2017.2;
Schönherr FA, Zehner T, Petrini O, LeibundGut-Landmann S, Fragoso Corti C. 2017. Low prevalence of Candida albicans in a local pediatric population and comparable genetic diversity in isolates from healthy and diseased individuals. Manuscript in preparation.
Personnes participant au projet
Dernière mise à jour de cette présentation du projet 04.10.2018