Final Report Summary - FUNMETA (Metabolomics of fungal diseases: a systems biology approach for biomarkers discovery and therapy)
Although humans have coevolved with ubiquitous or commensal fungi in host-fungus relationships that for the most part are positive or neutral, the clinical and economic burden of invasive fungal diseases is huge.
Diseases caused by opportunistic fungi have traditionally been viewed as the gross result of a pathogenic automatism which makes a weakened host more vulnerable to microbial insults. However, the increasing evidence that the microbiota is a crucial factor in the patient’s risk for infectious diseases suggests that the interplay between fungi and the mammalian host is more elaborated than previously appreciated. The results obtained in the ERC FUNMETA project have contributed in this direction by defining interactive processes between the host and its microbiota that govern fungal commensalism vs pathogenicity and providing proof-of-concept evidence of their drugability for therapeutic purposes. The tryptophan (trp) metabolic pathways crucially provided immune homeostasis in fungal infections by taming heightened inflammatory responses and inducing immune and tissue tolerance, an activity to which the host, fungi and the microbiota cooperatively contributed. The first step in mammalian trp catabolism is the cleavage of the 2,3-double bond of the indole ring of trp, a reaction performed independently by the indoleamine 2, 3–dioxygenase (IDO)1 and IDO2 (a paralogue of IDO1) and the tryptophan 2,3-dioxygenase, TDO2. On elucidating the relative contribution of the different mammalian dioxygenases in antifungal immunity and tolerance, we found it dependent on the combined effects of TDO2, IDO1 and the aryl hydrocarbon receptor (AhR), a ligand-operated transcription factor activated by L-kynurenine, the first by-product of trp catabolism in the kynurenine pathway. The IDO1/AhR pathway could be exploited therapeutically in mice and human preclinical settings by a number of biologicals (PTX3 and cytokines) and repurposed drug (anakinra and thymosin alpha 1), thus providing proof-of concept demonstration of drugability of host metabolic pathways for antifungal defenses. Fungi also resorted to their own IDO for their adaptability to the host environment. We found functional complementarity of mammalian and fungal IDOs in maintaining tissue homeostasis in infection and, at the same time, identified a fungal metabolic pathway implicated in pathogenesis and likely suitable for therapeutic purposes. We have then explored metagenomics to decipher the contribution of the microbiota to the AhR/IDO1-mediated immune tolerance to fungi and metabolomics to capture the dialogue between the host and the microbiota. By correlating changes in metabolite profiles with microbiota composition, we have defined a functional node in which IDO1 plays a dominant role in the interplay between trp catabolism by microbial communities, the host’s own pathway of metabolite production, and the orchestration of AhR-dependent immune homeostasis at mucosal surfaces. A bioactive indole—indole-3-aldehyde—(3-IAld) of microbial origin that contributed to AhR-dependent mucosal protection was discovered and patented for its therapeutic activity in protecting and maintaining mucosal integrity during fungal infections or chemical damage. The new classes of antifungal drugs have only been partly successful in improving the prognosis for patients with fungal infections and alternative therapies are urgently needed to overcome the pathology of fungal diseases. The drugability of the regulatory loop involving AhR and IDO1 for multi-pronged host- and microbiota-directed therapeutic approaches in human fungal infections makes the microbial indoles one of the greatest challenges in this field. Metagenomics, metabolomics and immunomics of patients at risk for fungal infections has revealed microbial signatures predictive of infection and detection of 3-IAld in human biological fluids could be a predictive marker of dysbiosis. Thus, through a multidisciplinary approach, this ERC project has provided scientific breakthroughs leading toward the definition of the immune-metabolic phenotype underlying multilevel host-fungus interactions in humans and translatable scientific knowledge with tremendous implications for personalized healthcare strategies.
Diseases caused by opportunistic fungi have traditionally been viewed as the gross result of a pathogenic automatism which makes a weakened host more vulnerable to microbial insults. However, the increasing evidence that the microbiota is a crucial factor in the patient’s risk for infectious diseases suggests that the interplay between fungi and the mammalian host is more elaborated than previously appreciated. The results obtained in the ERC FUNMETA project have contributed in this direction by defining interactive processes between the host and its microbiota that govern fungal commensalism vs pathogenicity and providing proof-of-concept evidence of their drugability for therapeutic purposes. The tryptophan (trp) metabolic pathways crucially provided immune homeostasis in fungal infections by taming heightened inflammatory responses and inducing immune and tissue tolerance, an activity to which the host, fungi and the microbiota cooperatively contributed. The first step in mammalian trp catabolism is the cleavage of the 2,3-double bond of the indole ring of trp, a reaction performed independently by the indoleamine 2, 3–dioxygenase (IDO)1 and IDO2 (a paralogue of IDO1) and the tryptophan 2,3-dioxygenase, TDO2. On elucidating the relative contribution of the different mammalian dioxygenases in antifungal immunity and tolerance, we found it dependent on the combined effects of TDO2, IDO1 and the aryl hydrocarbon receptor (AhR), a ligand-operated transcription factor activated by L-kynurenine, the first by-product of trp catabolism in the kynurenine pathway. The IDO1/AhR pathway could be exploited therapeutically in mice and human preclinical settings by a number of biologicals (PTX3 and cytokines) and repurposed drug (anakinra and thymosin alpha 1), thus providing proof-of concept demonstration of drugability of host metabolic pathways for antifungal defenses. Fungi also resorted to their own IDO for their adaptability to the host environment. We found functional complementarity of mammalian and fungal IDOs in maintaining tissue homeostasis in infection and, at the same time, identified a fungal metabolic pathway implicated in pathogenesis and likely suitable for therapeutic purposes. We have then explored metagenomics to decipher the contribution of the microbiota to the AhR/IDO1-mediated immune tolerance to fungi and metabolomics to capture the dialogue between the host and the microbiota. By correlating changes in metabolite profiles with microbiota composition, we have defined a functional node in which IDO1 plays a dominant role in the interplay between trp catabolism by microbial communities, the host’s own pathway of metabolite production, and the orchestration of AhR-dependent immune homeostasis at mucosal surfaces. A bioactive indole—indole-3-aldehyde—(3-IAld) of microbial origin that contributed to AhR-dependent mucosal protection was discovered and patented for its therapeutic activity in protecting and maintaining mucosal integrity during fungal infections or chemical damage. The new classes of antifungal drugs have only been partly successful in improving the prognosis for patients with fungal infections and alternative therapies are urgently needed to overcome the pathology of fungal diseases. The drugability of the regulatory loop involving AhR and IDO1 for multi-pronged host- and microbiota-directed therapeutic approaches in human fungal infections makes the microbial indoles one of the greatest challenges in this field. Metagenomics, metabolomics and immunomics of patients at risk for fungal infections has revealed microbial signatures predictive of infection and detection of 3-IAld in human biological fluids could be a predictive marker of dysbiosis. Thus, through a multidisciplinary approach, this ERC project has provided scientific breakthroughs leading toward the definition of the immune-metabolic phenotype underlying multilevel host-fungus interactions in humans and translatable scientific knowledge with tremendous implications for personalized healthcare strategies.