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Regulatory genes of antifungal resistance and their impact on fitness and virulence of pathogenic Candida species

English title Regulatory genes of antifungal resistance and their impact on fitness and virulence of pathogenic Candida species
Applicant Sanglard Dominique
Number 127378
Funding scheme Project funding
Research institution Institut de Microbiologie - CHUV Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Medical Microbiology
Start/End 01.03.2010 - 28.02.2013
Approved amount 537'000.00
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Keywords (6)

Candida; antifungal resitance; gene regulation; multidrug transporters; virulence; transcriptional activators

Lay Summary (English)

Lead
Lay summary
Infections caused by fungal pathogens belonging to Candida spp. (C. albicans and C. glabrata) are still a challenge to the medical practice. Despite available antifungals fungal diseases remain a threat to human health and especially in the population of immuno-compromised patients. As a consequence of antifungal treatment in patients, resistance can develop and compromise the success of the therapy. For the fungal pathogens, while development of resistance is associated with the persistence of the infection in the host, the adaptive mechanisms behind resistance development can significantly alter the capacities that are necessary to survive in the host, a notion also known under the term of "fitness cost". It is generally believed that development of antifungal resistance is associated with fitness costs in microbial pathogens which results in their decreased virulence. Our recent work has revealed in C. glabrata the unexpected association between antifungal resistance development and gain of fitness (and virulence) in animal models. Therefore our results challenge the dogma existing between these two phenomenons. In this research proposal, a detailed molecular analysis of the factors involved in the association between fitness and antifungal resistance will be undertaken. The work will first address this question both in C. glabrata and C. albicans. In C. glabrata, mutations in the transcription factor CgPDR1 (so called gain-of-function mutations, GOF) are participating to the upregulation of transporters involved in antifungal resistance. The occurrence of the same mutations enhances virulence and fitness in animal models. In this proposal, the entire set of C. glabrata genes regulated by GOF mutations will be obtained in order to identify genes responsible for gain of fitness and virulence. In C. albicans, several GOF mutations in transcriptional regulators are associated with resistance to antifungal agents. It is largely unknown whether GOF mutations in these transcriptional activators have a positive impact on the fitness and virulence of C. albicans in animal models. Using strains with identical genetic backgrounds, this work will attempt to answer this still opened question with the same approaches used for C. glabrata.In conclusion, our results are expected to highlight the costs or benefits of the development of antifungal resistance for host interactions in two major fungal pathogens. Identification of genes regulated by transcriptional regulator of antifungal resistance but involved in this critical balance if of interest because they might reveal key steps of fungal pathogenesis and can represent potential targets of future therapy.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence
Lohberger A Coste AT Sanglard D (2013), Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence, in Eukaryotic Cell, 13, 127-142.
Gain of function mutations in CgPDR1, a regulator of antifungal drug resistance in Candida glabrata, control adherence to host cells
Vale-Silva L., Ischer F., Leibundgut-Landmann S., Sanglard D. (2013), Gain of function mutations in CgPDR1, a regulator of antifungal drug resistance in Candida glabrata, control adherence to host cells, in Infect Immun, in press, xxx.
Milbemycins: more than efflux inhibitors for fungal pathogens
Silva L. V., Sanguinetti M., Vandeputte P., Torelli R., Rochat B., Sanglard D. (2013), Milbemycins: more than efflux inhibitors for fungal pathogens, in Antimicrob Agents Chemother, 57, 873-86.
Contribution of CgPDR1-Regulated Genes in Enhanced Virulence of Azole-Resistant Candida glabrata
Ferrari S, Sanguinetti M, Torelli R, Posteraro B, Sanglard D (2011), Contribution of CgPDR1-Regulated Genes in Enhanced Virulence of Azole-Resistant Candida glabrata, in PLOS ONE, 6(3), e17589-e17589.
In Vivo Systematic Analysis of Candida albicans Zn2-Cys6 Transcription Factors Mutants for Mice Organ Colonization
Vandeputte P, Ischer F, Sanglard D, Coste AT (2011), In Vivo Systematic Analysis of Candida albicans Zn2-Cys6 Transcription Factors Mutants for Mice Organ Colonization, in PLOS ONE, 6(10), e26962-e26962.
Loss of Mitochondrial Functions Associated with Azole Resistance in Candida glabrata Results in Enhanced Virulence in Mice
Ferrari S, Sanguinetti M, De Bernardis F, Torelli R, Posteraro B, Vandeputte P, Sanglard D (2011), Loss of Mitochondrial Functions Associated with Azole Resistance in Candida glabrata Results in Enhanced Virulence in Mice, in ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 55(5), 1852-1860.
Overcoming the heterologous bias: An in vivo functional analysis of multidrug efflux transporter, CgCdr1p in matched pair clinical isolates of Candida glabrata
Puri N, Manoharlal R, Sharma M, Sanglard D, Prasad R (2011), Overcoming the heterologous bias: An in vivo functional analysis of multidrug efflux transporter, CgCdr1p in matched pair clinical isolates of Candida glabrata, in BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 404(1), 357-363.

Collaboration

Group / person Country
Types of collaboration
Institute of Microbiology Catholic University of Sacred Heart Roma Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Hans Knoell Institute Jena (HKI) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss Society of Microbiology Poster Role of drug resistance transcription factors in Candida albicans virulence 21.06.2012 St-Gallen, Switzerland Lohberger Andrea;
International Society for Human and Animal Mycology Meeting (ISHAM) Talk given at a conference Effect of antifungal resistance on virulence of Candida spp.” 11.06.2012 Berlin, Germany Sanglard Dominique;
Candida and Candidiasis Talk given at a conference Antifungal resistant Candida glabrata isolate with enhanced virulence mediate d by CgPDR1 hyperactivity eva des phagocytosis by bone marrow-derived murine macrophages 29.03.2012 San Francisco, United States of America Vale Silva Luis;
Internatiomal Union of Microbiological Societies (IUMS) Talk given at a conference Antifungal drug resistance: diversity of mechanisms and consequences for microbial fitness 06.09.2011 Sapporo, Japan Sanglard Dominique;
Gordon Conferences on ABC transporters Talk given at a conference Participation of ABC transporters in drug resistance and virulence in the human pathogen Candida glabrata 15.06.2011 Les Diablerets (Suisse), Switzerland Sanglard Dominique;
Human Fungal Pathogens Talk given at a conference Antifungal resistance in Candida spp. 09.05.2011 La Colle-Sur-Loup (France), France Sanglard Dominique;


Associated projects

Number Title Start Funding scheme
146936 Identification of factors associated with antifungal resistance and fitness/virulence in pathogenic Candida species 01.04.2013 Project funding
114131 The response of the yeast pathogen Candida albicans to antifungal agents 01.10.2006 Project funding

Abstract

Infections caused by fungal pathogens belonging to Candida spp. (C. albicans and C. glabrata) are still a challenge to the medical practice. Despite available antifungal fungal diseases re-mains a threat to human health and especially in the population of immuno-compromised pa-tients. As a consequence of antifungal treatment in patients and exposure of the pathogens to antifungals, resistance can develop and compromise the success of the therapy. For the fungal pathogen, while development of resistance is associated with the persistence of the infection in the host, the adaptive mechanisms behind resistance development can significantly alter the capacities that are necessary to survive in the host, a notion also known under the term of “fit-ness cost”. It is generally believed that development of antifungal resistance is associated with fitness costs in microbial pathogens which results in their decreased virulence. Our recent work has revealed in C. glabrata the unexpected association between antifungal resistance de-velopment and gain of fitness (and virulence) in animal models. Therefore our results challenge the dogma existing between these two phenomenons. In this research proposal, a detailed molecular analysis of the factors involved in the associa-tion between fitness and antifungal resistance will be undertaken. The work will first address this question both in C. glabrata and C. albicans. In C. glabrata, mutations in the transcription factor CgPDR1 (so called GOF mutations for gain-of-function) are participating to the upregulation of at least ABC transporters involved in azole resistance. The occurrence of the same mutations results in enhanced virulence and fit-ness in animal models. In this proposal, the transcriptome of C. glabrata in the presence of GOF mutations in CgPDR1 will be obtained in order to identify genes responsible for gain of fitness and virulence. The candidate genes will be next inactivated to challenge their role as virulence factors in animal experiments. Genes with the desired phenotypes will be further characterized and their precise role in virulence/fitness further investigated by ex-vivo assays (endocytosis by macrophage/epithelial cells and fungal replication/survival). In C. albicans, several GOF mutations in transcriptional regulators are associated with resis-tance to antifungal agents. GOF mutations in TAC1, MRR1 are involved in the upregulation of multidrug transporters while those in UPC2 participates in the upregulation of sterol biosyn-thetic genes, among which ERG11, the target of azoles. It is largely unknown whether GOF mutations in these transcriptional activators have a positive impact on the fitness and viru-lence of C. albicans in animal models. Using strains with identical genetic backgrounds, this work will attempt to resolve this still unanswered question with the same approach than above-described for C. glabrata.In conclusion, our results are expected to highlight the costs or benefits of the development of antifungal resistance for host interactions in two major fungal pathogens. Identification of ge-nes regulated by transcriptional regulator of antifungal resistance but involved in this critical balance if of interest because they might reveal key steps of fungal pathogenesis and can rep-resent potential targets of future therapy.
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