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Background: The incidence of fungal infections in immuno-compromised patients has increased considerably over the last 30 years. Patients with systemic infections still show up to 30% of fatal issues and thus shows the limitation of available antifungals to treat these infections. Unfortunately, no considerable improvement of antifungal therapies has been developed recently. New treatments are therefore needed against pathogenic fungi. In human, Candida albicans is the most frequent fungal pathogen and also one of the most investigated. Host-fungal interactions play a critical role for any pathogen including C. albicans. Acting on this equilibrium can result in novel sources of therapies, which could be used alone or combined with existing antifungal drugs. Such a combination may also avoid the development of antifungal drug resistance. Aim: The present project is aimed to analyze the role of transcription factors (TF) in the interactions between C. albicans and its host. In this respect, TFs are of interest since they integrate several signals from the host environment and participate in an adapted microbial response. Among the yeast TFs, the classes of the “zinc cluster” TFs are of particular interest since they are specific to fungi and are crucial regulators of fungal physiology. These regulators and/or their downstream effectors constitute interesting targets for fungal inhibitors and are the focus of the present proposal Approaches: The proposed project will be divided into three parts. In the first part the colonization rate of C. albicans TF mutants will be measured in host organs using a mice model of systemic infection. For this purpose, an already existing collection of C. albicans transcription factor mutants we will be screened in a systemic mice model of infection. Each mutant will be specifically detected using a signature tags consisting of 40 nucleotides introduced in its genome. We will be then able to identify TFs necessary for mice organ colonization. In the second part of the project, at least 3 mutants identified in the first part of the project will be selected. Analyses using cultures of host cells will demonstrate the importance of these 3 TFs towards specific host immune effectors such as macrophages, neutrophiles, epithelium or endothelium barrier…. Additional analysis using a conditional expression of these TFs, meaning that we will be able to switch on or off the production of the TF during the course of infection in mice, will determine at which steps of the infection, TF are crucial for C. albicans colonization. In the last part of the project, we intend to determine by transcriptional genome-wide analysis the downstream target genes of the selected TFs, first in the context of in vitro cultures and next in vivo in infected tissues. These data will determine the metabolic pathways regulated by the selected TFs. Significance of the project This proposal will allow the identification of TFs important for the survival of C. albicans in the host. These identified factors and their downstream targets will reveal new C. albicans metabolic pathways and proteins critical for the survival of C. albicans to different host conditions. All these results will constitute models and generate a database for the study of fungal pathogenesis. It will allow a better understanding of host-fungal interactions, which may lead to the development of new treatment strategies.
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