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Alix Coste Lab
Alix Coste, PhD
++41 (0)21-3144061
alix.coste@chuv.ch
Research Topic
Virulence factors in pathogenic fungi
Candida albicans is an opportunistic pathogen causing oral, vaginal or systemic infections in immuno-compromized patients. Such patients, like HIV+, transplanted patients and those receiving chemotherapy, are in constant augmentation. In up to 30% of the patients with C. albicans systemic infections, the issue is fatal. Control of C. albicans infections is essentially achieved using treatments inhibiting microbial growth, such as treatment with azoles. For HIV+ and transplanted patients, long-time prophylactic and therapeutic antifungal treatment are needed. C. albicans exposed for a long time to these antifungals adapts to this stress, and develops resistance leading to treatment failure. Therefore, alternative treatment strategies are needed.
Host-pathogen interaction is a key component of any infectious process. Treatment modifying this relationship can be designed. Transcription factors (TF) are potentially important for C. albicans virulence since they integrate several signals from host environment and participate in an adapted microbial response.
In this project, we develop an original approach to analyze a collection of C. albicans transcription factor mutant strains in vivo. A collection of TF mutant strains are screened in a mice model of systemic infection in order to identify those factors crucial for virulence. Additional analysis is performed on the selected TF to understand at which steps of the infection they are involved and which element of the host defense they target.
Genes under the control of those TF will then be identified in order to determine which metabolic pathways of the fungus are involved in the infection.
This analysis is important for C. albicans infection but will constitute a model for other pathogenic fungi. A mid-term outcome of this project will be a better understanding of the global host-fungus interactions, which may lead to the development of new drugs and treatment strategies.
2010
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Maccallum DM, Coste A, Ischer F, Jacobsen MD, Odds FC, Sanglard D.
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Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated
Antimicrob Agents Chemother. 2010 Jan 19. |
2009
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Coste AT, Crittin J, Bauser C, Rohde B, Sanglard D.
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Functional analysis of cis- and trans-acting elements of the Candida albicans CDR2 promoter with a novel promoter reporter system.
Eukaryot Cell. 2009 Jun 26. |
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Sanglard D, Coste A, Ferrari S.
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Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation.
FEMS Yeast Res. 2009 Oct;9(7):1029-50. |
2008
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Coste AT, Ramsdale M, Ischer F, Sanglard D.
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Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae.
Microbiology. 2008 May;154(Pt 5):1491-501. |
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Gobert AP, Coste A, Guzman CA, Vareille M, Hindré T, de Sablet T, Girardeau JP, Martin C.
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Modulation of chemokine gene expression by Shiga-toxin producing Escherichia coli belonging to various origins and serotypes.
Microbes Infect. 2008 Feb;10(2):159-65. |
2007
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Coste AT, Ischer F, Forche A, Semelcki A, Berman J, Diogo D, D’Enfert C, and Sanglard D.
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Genotypic evolution of drug resistance mechanisms in sequential C. albicans isolates.
Eukaryot Cell. 2007 Oct;6(10):1889-904. |
2006
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Coste AT, Turner V, Ischer F, Morschhäuser J, ForcheA, Semelcki A, Berman J, Bille J, and Sanglard D.
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A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at Chromosome 5 to mediate antifungal resistance in Candida albicans.
Genetics, 2006 Apr;172(4) : 2139-56 |
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Karababa M, Valentino E, Pardini G, Coste AT, Bille J, and Sanglard D.
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CaCRZ1, a target of the calcineurin pathway in Candida albicans.
Mol. Microbiol. Mar;59(5):1429-51 |
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Pardini G, De Groot PW. Coste AT, Karababa M, Klis FM, de Koster CG, Sanglard D.
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The CRH family coding for cell wall glycosylphosphatidylinositol proteins with a predicted transglycosidase domain affects cell wall organization and virulence of Candida albicans.
J Biol Chem. 2006 Dec 29;281(52):40399-411 |
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Rognon B, Kozovska Z, Coste AT, Pardini G, and Sanglard D.
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Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans, a Major Facilitator transporter involved in azole resistance.
Microbiology. 2006 Dec;152(Pt 12):3701-22. |
2004
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1: |
Coste AT, Karababa M, Ischer F, Bill J, Sanglard D.
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TAC1 (Transcriptional Activator of CDR genes) is a new transcription factor involved in the regulation of the Candida albicans ABC-transporters CDR1 and CDR2.
Eukaryot Cell. 2004 Dec;3(6):1639-52 |
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Karababa M, Coste AT, Rognon B, Bille J, Sanglard D.
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Microarrays Comparison of gene expression profiling in Candida albicans azole-resistant clinical isolates and in laboratory strains exposed to drugs inducing multidrug transporters.
Antimicrob Agents Chemother. 2004 Aug;48(8):3064-79. |
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