Yeast on our Skin: Decision Makers between Homeostasis and Cutaneous Allergy

Skin diseases have a high global prevalence. Although usually not lethal, they significantly limit the well-being of those affected and consequently are listed the 4th greatest non-fatal disabling condition, with atopic dermatitis (AD) and dermatomycoses ranking among the most frequent skin pathologies. AD is a chronic-relapsing pruritic disorder affecting up to 20% of children and 10% of adults in developed countries. AD often precedes other allergic morbidities, (allergic rhinitis, asthma), thereby significantly enhancing the disease burden with high psycho-social (anxiety, depression, social withdrawal) and socio-economic burden. There is currently no cure for AD. While the introduction of targeted systemic immunomodulatory therapy has been a game-changer for many moderate/severe AD patients, we still face 10-25% treatment failures. AD therefore represents a major public health issue with a large unmet medical need and requires research investment to generate tractable innovations to mitigate these health burdens. AD skin is characterized by barrier defects and sensitization against normally harmless environmental antigens, including components of an individual’s own microbiota. While the pathogenic role of Staphylococcus aureus in AD is well established, that of skin fungi is not. The skin mycobiota is unique as it is dominated by members of a single fungal genus, Malassezia, which display remarkable diversity. Understanding how the prevalent commensal skin fungus Malassezia becomes a target of the hypersensitivity response in atopic skin and thereby contributes to disease pathogenesis will open new avenues in AD therapy that target the mycobiome to overcome current treatment failures. Given the emergence of antifungal resistance and the pre-existing resistance of many Malassezia strains to common antifungal agents, more specific strategies to target Malassezia are required, and for this, a better understanding of the dysfunctional fungus-host interaction in AD is essential. This programme builds on established collaborations and brings together world-leading experts in immunology, mycology, and dermatology to test the hypothesis that in addition to host factors, variation in Malassezia genotype or phenotype contributes to the dysfunctional host-fungus interaction underlying AD. In support of this hypothesis, Malassezia exhibits a remarkable degree of strain variation which segregates according to their healthy vs. atopic skin habitat. The key objectives of this programme are to: Define the fungus-host interface responsible for driving immunosurveillance of the skin commensal yeast Malassezia during homeostasis. Identify fungal pathogenicity determinants underlying the dysfunctional host-microbe interaction in AD that results in sensitization to Malassezia. Inform whether modulating the skin mycobiome, and targeting the Malassezia-host interface in particular, may benefit difficult-to-treat AD patients and overcome treatment failure. Using Malassezia isolates from AD patients and genetically tractable laboratory strains of Malassezia in combination with clinical data and experimental disease models we aim to identify key fungal determinants underlying the immunopathological outcome of the fungus-host interaction in AD skin. At the intersection of medical mycology, dermatology, and allergology and by combining basic and clinical research, this programme will generate fundamental new insights into the host-fungus crosstalk in skin, providing a new perspective on the pathogenesis of AD. It will further propose new targets for the prevention and treatment of one of the most common skin diseases including treatment resistant AD. This in turn will pave the way for precision medicine interventions in patient management through preventive or therapeutic targeting of the mycobiome or altered downstream host-interaction pathways.