Introduction
Galar Fungail means "Fungal Disease" in Gaelic, the language of the Scottish Celts. Galar Fungail is the acronym for a European project on Novel Approaches for the Control of Fungal Disease. This project is funded by the Framework Programme 5 of the European Commission under Key Action 2.2 (Strategies to Identify and Control Infectious Diseases).
Candida albicans is the major fungal pathogen in humans. It causes frequent, recurrent and irritating superficial infections, particularly in women and HIV patients (thrush). This fungus also causes serious and often fatal systemic infections in immunocompromised patients. These infections seriously affect the quality of life and health of the European population. Our overall objective is to advance our understanding of C. albicans biology and pathogenesis significantly. This will provide a strong platform for the development of new antifungal therapies.
In the early stages of the project, C. albicans genome arrays will be manufactured and samples will be collected for transcript profiling. In parallel, the regulatory hierarchies that control the expression of major virulence factors will be investigated, and a novel screen will be developed for human factors and C. albicans proteins that interact physically with each other. The C. albicans arrays will then be used to perform transcript profiling on wild type C. albicans cells grown in vitro, on regulatory mutants, and on cells isolated from infected tissues. This will identify sets of fungal genes that respond to specific environmental stimuli, and fungal genes that are expressed specifically during infections. These data sets will be compared to construct regulatory models that account for the observed patterns of gene regulation. Also, the new interaction screen will be performed to identify novel interactions between host factors and C. albicans proteins. The latter stages of the project will involve an iterative process of model building, experimental testing, and model refinement with a view to building accurate models that describe specific aspects of fungus-host relationships during the disease process. This will exploit a new relational C. albicans genomics database, built during this project for the comparison of our data with other C. albicans genome data. This database will provide the basis for the exploitation of our large data set for improvements in antifungal therapy.
Highlights
of the first two years of the Galar
Fungail Consortium
Annotation
of the C. albicans genome sequence
generated by the Stanford DNA
Sequencing and Genome Technology Center.
Public
release of this genome annotation in CandidaDB
Patent
on the design of whole genome C. albicans microarrays based on our genome annotation.
Commercialization
of the C. albicans array design
through our Subcontractor, Eurogentec,
who are now selling the arrays.
Use
of C. albicans arrays for the
transcript profiling of regulatory mutants,
in vitro growth conditions, and
cells growing in infection models.
Identification
of C. albicans genes that are
regulated in response to morphogenetic regulators, chromatin remodeling,
environmental triggers and fungus-host interactions.
Significant
advances in our understanding of morphogenetic regulation in C.
albicans: autoregulation of Efg1; identification and characterization of
Gpa2; negative regulation by Nrg1; activation by Gcn4; influence of
chromatin remodeling factors.
Significant
progress in our understanding of C. albicans cell wall architecture: in silico identification of cell wall proteins; identification of
new cell wall components required for C.
albicans virulence; characterization of mannoprotein-carbohydrate
linkages in cell wall biogenesis.
Significant
progress in our understanding of the regulation and functions of SAP gene
family members.
Development
of a new FLP-based recombination system for the C.
albicans molecular toolbox.
Organization
of EURESCO conferences on Human Fungal Pathogens (Seefeld in 2001; Giens in 2003).
21
publications on Galar Fungail work.
Brown,
A.J.P.
(2002) Expression of growth form-specific factors during morphogenesis in Candida
albicans. In “Candida and
Candidiasis” (Calderone, R., ed.) ASM Press, pp 87-93.
Brown, A.J.P. (2002) Morphogenetic signalling pathways in Candida albicans. In “Candida and Candidiasis” (Calderone, R., ed.) ASM Press, pp 95-106.
Ernst,
J. F., and D. P. Bockmühl. 2001. Gene expression and genetic
Felk,
A., Kretschmar, M., Albrecht, A., Schaller, M., Beinhauer, S., Nichterlein,
T., Sanglard, D., Korting, H. C., Schäfer, W., and Hube,
B. (2002) Candida albicans
hyphal formation and the expression of the Efg1-regulated proteinases Sap4-6
are required for the invasion of parenchymal organs. Infection
& Immunity 70, 3689-3700.
[Medline]
Fradin,
C., Kretschmar, M., Nichterlein, T., Gaillardin,
C., d'Enfert, C., and Hube, B.
(2002) Stage-specific gene expression of Candida
albicans in human blood. Molec.
Microbiol. 47:1523-1543. [Medline]
De Groot, P.W., Hellingwerf, K.J., Klis F.M. (2003) Genome-wide identification of fungal GPI proteins. Yeast 20:780-793. [Medline]
Hube,
B., Stehr,
F., Bossenz, M., Mazur, A., Kretschmar, M. and Schafer, W. (2000) Secreted
lipases of Candida albicans:
cloning, characterisation and expression analysis of a new gene family with
at least ten members. Arch. Microbiol.
174, 362-374. [Medline]
Hube,
B. and
Naglik, J. (2001) Candida albicans
proteinases: resolving the mystery of a gene family. Microbiology
147, 1997-2005. [Medline]
Hube,
B.
and Naglik, J. (2002). Extracellular Hydolases. In
“Candida and Candidiasis” (Calderone,
R., ed.) ASM Press.pp. 107-122.
Klis,
F.M., De
Groot, P. and Hellingwerf, K. (2001) Molecular organization of the cell wall
of Candida albicans. Med. Mycol. 39, 1-8. [Medline]
Klis,
F.M., Mol, P., Hellingwerf, K.
and Brul, S. (2002) Dynamics of cell wall structure in Saccharomyces cerevisiae. FEMS
Microbiol Rev. 26, 239-256. [Medline]
León,
M., Sentandreu, R. and Zueco, J.
(2002) A single FKS homolog in Yarrowia
lipolytica is essential for viability. Yeast
15, 1003-1014. [Medline]
Munro,
C., and Hube, B. (2002). Antifungal therapy at the HAART of viral therapy. Trends
in Microbiol.
10, 173-177. [Medline]
Murad,
A. M., C. d'Enfert, C. Gaillardin,
H. Tournu, F. Tekaia, D. Talibi, D. Marechal, V. Marchais, J. Cottin, and A.
J. P. Brown. (2001)
Transcript profiling in Candida
albicans reveals new cellular functions for the transcriptional
repressors CaTup1, CaMig1 and CaNrg1. Molec. Microbiol. 42, 981-93. [Medline]
Murad,
A.M.A., Leng, P., Straffon, M., Wishart, J., Macaskill, S., MacCallum, D.
Schnell, N., Talibi, D., Marechal,
D., Tekaia, F., d’Enfert, C.,
Gaillardin, C., Odds, F.C. and Brown,
A.J.P. (2001) NRG1 represses
yeast-hypha morphogenesis and hypha-specific gene expression in Candida
albicans. EMBO.
J. 20, 4742-4752. [Medline]
Orozco,
I., Ortiz, L., Elorza, M.V., Ruiz-Herrera, J. and Sentandreu,
R. (2002) Cloning and characterization of PBR1,
a Candida albicans gene encoding a
putative novel endoprotease B and factors affecting its expression. Research
in Microbiol., In press. ??? [Medline]
Richard,
M., de Groot, P., Courtin, O., Poulain, D., Klis,
F. and
Gaillardin, C.
(2002) GPI7 affects cell-wall protein anchorage in Saccharomyces cerevisiae and Candida
albicans. Microbiology 148,
2125-2133. [Medline]
Richard,
M., Ombetta, S.I., Dromer, F., Bordon-Pallier, F., Jouault, T. and Gaillardin,
C.
(2002) Complete glycosylphosphatidylinositol anchors are required in Candida albicans for full morphogenesis, virulence and resistance to
macrophages. Molec. Microbiol. 44,
841-853. [Medline]
Richard,
M., Rosas Quijano, R., Bezzate, S., Bordon-Pallier, F. and Gaillardin,
C.
(2001) Tagging morphogenetic genes by insertional mutagenesis in the yeast Yarrowia lipolytica. J.
Bacteriol. 183, 3098-3107. [Medline]
Ruiz-Herrera,
A., Martinez, I. and Sentandreu, R.
(2002) Determination of the stability of protein pools from the cell all of
fungi. Research in Microbiol. 153,
373-378. [Medline]
Sánchez-Martínez,
C. and Pérez-Martín, J.
(2002) Gpa2, a G-protein a subunit that is required for hyphal development
in Candida albicans. Eukaryotic
Cell 1:865-874 [Medline]
Sánchez-Martínez,
C. and Pérez-Martín, J.
(2002) Site-specific targeting of exogenous DNA into Candida albicans genome by use of the FLP recombinase. Mol.
Gen. Genomics, 268:418-24. [Medline]
Tebarth,
B., T. Doedt, S. Krishnamurthy, M. Weide, F. Monterola, A.
The project is being executed by a Consortium comprising the following research groups:
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