Humans have evolved intimate symbiotic relationships with a consortium of gut microbes (including fungi) and individual variations in the microbiome influence host health and disease. The fact that fungi are capable of colonizing almost every niche within the human body suggests that they must possess particular immune adaptation mechanisms, the breakdown of which may result in fatal fungal infections and severe fungal diseases. Traditional reductionist approaches of the past have not been sufficient to address these new challenges in the pathogenesis of fungal diseases. Here, I propose an integrated, systems biology approach to understand the role of L-tryptophan (trp) metabolic pathways in multilevel host−fungus interactions. Present in mammals as well as in fungi, pathways of trp metabolic pathways are exploited by the host and the fungal biota for survival and immune adaptation. A variety of indole derivatives, generated through conversion from dietary trp by symbiotic bacteria, activate the aryl hydrocarbon receptor/IL-22 pathway that provides antifungal resistance and tissue repair. Harmful inflammatory responses to fungi are instead tamed by kynurenines generated via the enzyme indoleamine 2,3–dioxygenase (IDO) of the trp pathway. Through high-throughput wet-lab ‘omics’ techniques combined with computational techniques, the project aims at defining the molecular basis of mammalian and fungal IDO activity and a metabolic network linking the metabolic phenotype (metabotype) to immune adaptations and its possible breakdown in experimental and human fungal infections. The project will provide ideal post-graduate training focussed on the development of metabolomics for diagnosis of fungal diseases and optimization of current antifungal therapy and diet that are of relevance to public health care solutions.
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Meccanismo di finanziamentoERC-AG - ERC Advanced Grant
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