Project

Back to overview

Genome wide analysis of the role of transcription factors of Candida albicans in the survival in host conditions

English title Genome wide analysis of the role of transcription factors of Candida albicans in the survival in host conditions
Applicant Coste Alix
Number 139605
Funding scheme Marie Heim-Voegtlin grants
Research institution Institut de Microbiologie - CHUV Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Experimental Microbiology
Start/End 01.06.2012 - 31.05.2014
Approved amount 200'332.00
Show all

All Disciplines (5)

Discipline
Experimental Microbiology
Molecular Biology
Cellular Biology, Cytology
Immunology, Immunopathology
Medical Microbiology

Keywords (7)

transcription factors; Candida albicans; virulence; animal model; host-pathogen interaction; immune response; organ colonisation

Lay Summary (English)

Lead
Lay summary

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.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Adaptation of a Gaussia princeps Luciferase reporter system in Candida albicans for in vivo detection in the Galleria mellonella infection model
Eric Delarze Françoise Ischer Dominique Sanglard & Alix T Coste (2015), Adaptation of a Gaussia princeps Luciferase reporter system in Candida albicans for in vivo detection in the Galleria mellonella infection model, in Virulence, 6(7), 684-693.
Examining the virulence of Candida albicans transcription factor mutants using Galleria mellonella and mouse infection models
Sara Amorim-Vaz Eric Delarze Françoise Ischer Dominique Sanglard* and Alix T. Coste (2015), Examining the virulence of Candida albicans transcription factor mutants using Galleria mellonella and mouse infection models, in Frontiers in Microbiology, 6, 367.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
12th ASM Conference Candida and Candidiasis Talk given at a conference Mini-host and mouse infection models for probing virulence of Candida albicans transcription factors mutants. 26.03.2014 New-Orleans, United States of America Coste Alix;
-Annual Assembly of the Swiss Society of Microbiology and Swiss yeast meeting Poster Analysis of two C. albicans Zn2-Cys6 transcription factors required for host colonization 26.06.2013 Interlaken, switzerland, Switzerland Coste Alix;
5th FEBS Advanced Lecture Course Human Fungal Pathogens : Molecular Mechanisms of Host-Pathogen Interactions and Virulence Poster Analysis of two C. albicans Zn2-Cys6 transcription factors required for host colonization 25.05.2013 La Colle sur Loup, France, France Coste Alix;
ISHAM meeting Talk given at a conference Analysis of two C. albicans Zn2-Cys6 transcription factors required for host colonization 11.06.2012 Berlin, Germany, Germany Coste Alix;


Self-organised

Title Date Place
5th day of continuing education for animal experimentation of the Research of Department Laboratories of the CHUV 23.05.2014 Lausanne, Switzerland
4th day of continuing education for animal experimentation of the “ CHUV Research of the Department Laboratories 24.06.2013 Lausanne, Switzerland, Switzerland

Associated projects

Number Title Start Funding scheme
141848 Novel genome-wide transcriptomic approaches to challenge Candida albicans-hosts interactions 01.01.2013 Sinergia

Abstract

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. 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, which 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 vivo. Each mutant will be specifically detected using signature tags and thus TFs necessary for mice organ colonization will be identified. In the second part of the project, at least 3 mutants identified in the first part of the project will be selected. Using ex vivo analyses, the importance of these 3 TFs towards specific host immune effectors will be assessed. Additional analysis using a conditional expression of these TFs will be performed to determine in vivo at which steps of the infection they 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. 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.
-