Candida: Comparative and Functional Genomics
"well written, clear and extremely well referenced" (The Biochemist)
Caister Academic Press
and Bernhard Hube2
1Unité Postulante Biologie et Pathogénicité Fongiques, Institut Pasteur, 75724 Paris Cedex 15, France and 2Robert Koch-Institut, Nordufer 20, D-13353 Berlin, Germany
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Candida species are important human pathogens that are best known for causing opportunist infections in immunocompromised hosts (eg transplant patients, AIDS sufferers, cancer patients). Infections are difficult to treat and can be very serious: 30-40% of systemic infections result in death. The sequencing of the genome of C. albicans and those of several other medically-relevant Candida species has provided a major impetus for Candida comparative and functional genomic analyses. These have provided a fascinating insight into the molecular and cellular biology of these fungi and these should pave the way for the development of more sensitive diagnostic strategies and novel antifungal therapies.
In this timely book international experts provide comprehensive and authoritative reviews of these important organisms. Topics covered include: genome dynamics of C. albicans; molecular epidemiological and population studies of C. albicans; the parasexual cycle in C. albicans; comparative genomics of the hemiascomycetes group and of different Candida species; databases and the challenges that their curators are facing; transcriptome analysis; proteomics; molecular evolution of the genetic code; stress responses; regulation of morphogenesis; cell wall biology; interaction with host cells; analysis of gene function; antifungal resistance mechanisms and much more.
Essential reading for all Candida genome and molecular biology researchers and a recommended text for scientists working on fungal genomics and molecular biology.
"an excellent opportunity to catch up ... I found reading this book a most enjoyable experience ... very clearly written" from Jan Schmid, IMBS, Massey University, Palmerston North, New Zealand
"It contains an abundance of detailed information that will be useful to scientists working in this field. Overall, it will serve as a reference in this field for a long time." from Doodys
"... the most complete and authoritative review on Candida ... an invaluable resource for all Candida molecular biology researchers. It is expensive, but a very worthwhile institutional purchase." from Microbiology Today (2007)
"... essential reading for all Candida genome and molecular biology researchers and is a recommended text for scientists working on fungal genomics and molecular biology... recommended for a wide range of scientists interested in the biology of yeasts, fungal infections and also the basic mechanisms of the eukaryotic cell." from International Microbiology (2007) 10: 296-297.
"The book is well written, clear and extremely well referenced ... This book works well because it contains one central premise; the understanding of molecular mechanisms behind the pathogenic Candida. Retailing at £159, this is an inexpensive price for good science." from The Biochemist (July 2014)
Table of contents
1. Genome Structure and Dynamics in Candida albicans
Candida albicans is an obligate diploid with 8 pairs of chromosomes ranging in size from 0.95 to 3.5 Mb, amounting to a haploid complement of 16 Mb of DNA. The genome has a number of features which are rare among fungi. Among these are a complex repeat (the MRS) which occurs, at least in part, on every chromosome and is a frequent site of chromosomal translocation, the stress-induced loss of one of several chromosome homologues with a subsequent effect on phenotype, the involvement of homologous recombination in telomere maintenance, and a centromere which lacks any obvious repeat sequences. There is an exceptional amount of heterozygosity in the genome. Although mating has been demonstrated in the laboratory, no meiosis has been reported. No clinical isolates with the 4N ploidy of the mating products have been recovered, and tetraploids constructed in the laboratory are rapidly outcompeted by diploids in experimental infections. Evidence for recombination, obtained by haplotype analysis, seems most likely to be due to mitotic recombination, which occurs at about the same frequency as in Saccharomyces cerevisiae in the laboratory. The emerging completed sequence and the availability of a single nucleotide polymorphism (SNP) map, with markers spaced at about 100 kb, for the entire genome will facilitate further elucidation of the interesting genome dynamics of this important human pathogen.
2. The Mating Type Locus, Switching and Mating in Candida
David R. Soll
In 1999, the mating type-like (MTL) locus of Candida albicans was characterized, and in 2000, mating was demonstrated in vitro and in vivo. These discoveries demonstrated a functional mating system in C. albicans. In the years that followed, similarities to the Saccharomyces cerevisiae mating system were identified, but more interestingly, unique features were demonstrated, including a1-α2 repression of white-opaque switching, the requirement of a phenotypic switch from white to opaque to attain mating competency, the incorporation of the program of filamentation into the mating process, and the signaling of white cells by opaque cells through the release of pheromone, to form a biofilm presumably to facilitate mating. The mating system of Candida dubliniensis mimics that of closely related C. albicans, while that of Candida glabrata mimics that of closely related S. cerevisiae. The mating systems of C. albicans, C. dubliniensis and C. glabrata are reviewed with attention to the possible relationships they may have to pathogenesis.
3. Molecular Epidemiology and Population Dynamics in Candida albicans
Marie-Elisabeth Bougnoux, Dororthée Diogo, Claude Pujol, David R. Soll and Christophe d'Enfert
is a heterozygous diploid species that has a predominantly clonal mode of reproduction despite the occurrence of a parasexual cycle. Molecular typing through fingerprinting of genomic DNA with the Ca3 probe has shown that the C. albicans
population is divided in five major clades. More recently, multi-locus sequence typing data have indicated the occurrence of additional clades. Clade-specific phenotypes, exemplified in the context of antifungal susceptibility and structure of adhesion molecules, have been identified. Thus, future research on C. albicans
should take into account the population structure and expand genome sequencing and investigation of the impact of genetically-engineered mutations to representative isolates of the different clades.
Recombination between clades and within clades is marginal and heterozygous genotypes appear predominant. Characterization of closely-related isolates that have undergone micro-evolution suggest that these occur mostly through spontaneous or induced karyotype alterations and/or loss of heterozygosity. Because heterozygous genotypes are predominant in the C. albicans
population while spontaneous loss of heterozygosity is relatively frequent, it is likely that heterozygosity confers a selective advantage to C. albicans
4. Comparative Genomics in Hemiascomycetous Yeasts
Héloïse Muller, Bernard Dujon and Cécile Fairhead
The sequence of Sacharomyces cerevisiae, or baker's yeast, an omnipresent genetic model in research laboratories, was released in 1996, thanks to the work of multinational consortia. This was the first complete sequence of a eukaryotic organism, and led to the discovery of many new genes, paving the way for sequence analysis of its closest sibling species, the hemiascomycetes. Since then, many hemiascomycetes have been completely or partially sequenced, offering a unique panel of genomic sequences from phylogenetically close species. We review here the major features revealed by these sequences; genome size and gene number, chromosomal structures such as centromeres, telomeres and replication origins, and we discuss the evolutionary paths that led to differing genome compositions in these species, including the whole genome duplication that occurred in the Saccharomyces branch, chromosomal rearrangements and divergence in protein-coding genes.
5. Comparative Genomics of Candida Species
Geraldine Butler and Derek J. Sullivan
The complete genome sequences of Candida albicans and of four other hemiascomycetes (including C. glabrata and Debaryomyces hansenii) was reported in 2004. Currently, high quality draft sequence is either available or in progress for six species related to C. albicans, including C. dubliniensis, C. tropicalis, C. parapsilosis, Lodderomyces elongisporus, C. (or Pichia) guilliermondii, and C. (or Clavispora) lusitaniae. In addition sequencing the genome of a second isolate of C. albicans is also underway. This will generate an extremely valuable resource, as both pathogenic (C. albicans, C. tropicalis, C. parapsilosis, C. lusitaniae, C. glabrata) and non-pathogenic (D. hansenii, L. elongisporus, C. guilliermondii) are included. The species list also includes a number that are apparently asexual (such as C. albicans) and some that are fully sexual (such as C. guilliermondii and L. elongisporus). This chapter describes the progress of the various genome sequencing projects and their current status. The relationship and possible evolution of the Mating Type-Like locus is also discussed.
6. Global Transcription Profiles of C. albicans and the Comparison of Other Yeast Species
Sven Bergmann, Jan Ihmels and Judith Berman
In addition to providing an inventory of genes and their regulatory regions, whole-genome sequencing has paved the way for high-throughput technologies that take snapshots of the regulatory programs governing the expression of these genes. Analyzing many different C. albicans transcription profile experiments revealed global patterns of gene expression that would have been difficult to glean from individual studies. A next step is to compare these global patterns between organisms; comparison to S. cerevisiae global expression patterns is particularly useful because of the large datasets available. The Differential Clustering Algorithm (DCA) is a flexible algorithm that systematically analyzes differences, as well as similarities, in gene expression patterns. It was used to identify important aspects of the transcriptional networks that have been rewired through the evolution of S. cerevisiae and C. albicans. Specific examples of changes in the patterns of expression of cell cycle genes and amino acid biosynthesis genes are detailed. Analysis of the evolution of a promoter sequence motif associated with rapid growth metabolism is also considered.
7. Molecular Evolution of the Candida Genetic Code
Gabriela Moura, Tatiana Lima-Costa, Laura Carreto, Ana C. Gomes and Manuel A. S. Santos
The leucine CUG codon is decoded as serine in many Candida species. The reassignment of this leucine codon to serine is a unique genetic event that occurred 272 +/- 25 million years ago and reprogrammed the identity of 25-30,000 CUG codons that existed in the Open Reading Frames (ORFeome) of the ancestor of yeasts. Using comparative genomics methodologies, we were able to partially reconstruct the evolutionary pathway of CUG reassignment from leucine to serine. This genetic code change had a major impact on the usage of the leucine CUN and UUA, UUG codons and forced the disappearance of most CUG codons of the Candida ancestor. In other words, the CUG codons present in extant Candida species are not related to those present in the ORFeomes of other yeasts, namely S. pombe and S. cerevisiae. Furthermore, most of these new CUG codons are located in fast evolving genes and in genes that encode small open reading frames. The genetic code of Candida species has been subjected to unique evolutionary forces whose molecular nature is not yet fully understood.
8. Candida albicans Genomics Resources and Tools
Marek S. Skrzypek, Martha B. Arnaud, Maria C. Costanzo and Gavin Sherlock
The genomic age has yielded exciting opportunities for the understanding of biological processes with greater breadth and depth than before, and concomitant, exponential increases in the amount of data being generated on a routine basis. Genome databases collect, organize, display, and provide tools to analyze and explore the otherwise potentially overwhelming amount of information available, and they are therefore necessary for research communities to fully take advantage of the data. In this chapter, we survey the database resources available to the Candida albicans genomics research community, discuss the types of information available in these databases, and consider additional resources and tools that will need to be developed to effectively deal with additional data types that will be generated in the future.
9. Proteomics in Candida species
Aida Pitarch, Gloria Molero, Lucía Monteoliva, Derek. P. Thomas, José Luis López-Ribot, César Nombela and Concha Gil
Proteomics may significantly contribute towards a better understanding of the biological complexity encoded by the Candida genome and, in short, of Candida pathogenicity. From the first steps in the Candida proteome analysis in the early 1980s to the present time, the potential of this discipline to contribute to Candida investigations is being increasingly recognised. In fact, the recent availability of the complete C. albicans and C. glabrata genome sequences together with improvements in proteomics-based technologies are currently enabling the systematic characterization of the proteome for these two human pathogens. Remarkably, Candida proteome analyses have so far helped to unravel novel concepts in the cell envelope, virulence factors (including dimorphism and adhesion), host responses (antibody and macrophage responses) and drug resistance, among others. These results portend a near future in which proteomic technology is an indispensable tool in Candida research. It may be the rosetta stone that sheds light on certain Candida paradigms that are not predictable at this moment from genomic studies.
10. From Genes to Function: Systematic Approaches Used to Study Candida albicans and Candida glabrata Biology and Pathogenesis
Arnaud Firon and Christophe d'Enfert
Genome sequencing has revolutionized the approaches that are used to tackle various aspects of the biology of eukaryotic micro-organisms. In particular, it is now possible to establish collections of mutant strains with systematic inactivation or tagging of all the genes that have been identified through in silico analysis of the genome sequence. Subsequent characterization of the mutant strains in individual tests or in pools using signature tagged mutagenesis screens provides a rapid and systematic evaluation of the contribution of all genes to a particular biological process. Functional genomics, pioneered in S. cerevisiae, is now within reach for Candida albicans, Candida glabrata and possibly other Candida species whose genomes have been sequenced. For example, transposon-mutagenesis or targeted mutagenesis have been used to generate collections of knock-out or conditional mutants in C. albicans and C. glabrata and show considerable promise for the identification of virulence factors as well as novel targets for the development of antifungals. In parallel, complementary information on host-fungus interactions are provided by systematically altering gene function in host cells through methodologies such as RNA interference.
11. Stress Responses in Candida albicans
Janet Quinn and Alistair J.P. Brown
The virulence of the Candida albicans is dependent upon its ability to mount stress responses. This reflects the importance of these responses in protecting this fungal pathogen against host defenses. Recent genomic studies have contributed significantly to our understanding of stress responses in C. albicans and how they are regulated. It has become clear that C. albicans has diverged significantly from the benign model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe with respect to the nature and regulation of its stress responses. C. albicans appears to utilize classical molecular mechanisms to protect itself against oxidative, osmotic, heat and heavy metal stresses. These include the synthesis of anti-oxidants, osmo-protectants and chaperones, for example. However, the Core Transcriptional Response to stress seen in C. albicans differs significantly from that observed in budding and fission yeasts. Furthermore, although key regulatory molecules are conserved in C. albicans, their contributions to the regulation of stress responses have diverged.
12. Regulation of Morphogenesis in Candida species
Sabine E. Eckert, Chirag C. Sheth and Fritz A. Mühlschlegel
The human pathogen Candida albicans can grow as yeast, pseudohyphae, and true hyphae. This article aims to present an overview of recent research into the regulation of processes underlying morphogenesis in response to external influences. We present a summary of known and novel environmental factors determining cell shape. Our principal focus is to explain the increasing complexity of and relationship between signal transduction pathways, especially new proteins involved in or connected with the Ras1-dependent pathways. We further present recent results from the Tup1/Nrg1/Rfg1 group of regulators, the Hog1 and the protein kinase C pathways, and the influence of pH on morphogenesis. We review factors not presently connected to known networks, and those that influence cell morphology while having other primary functions, e.g. regulation of the cell cycle. We conclude by presenting the recent research on CO2 as a newly described inducer of filamentation in C. albicans.
13. Cell Wall Biology of Candida
Piet W.J. de Groot, Bernd W. Brandt and Frans M. Klis
Fungal cell walls play a crucial role in maintaining osmotic homeostasis and offer protection against mechanical damage; they also play a key role in the initial events that take place during the establishment of fungal infections. Cell wall architecture and biosynthesis have been extensively studied in Saccharomyces cerevisiae and later also in Candida albicans, resulting in a detailed molecular model of their walls. Genome sequencing of several Candida species has been completed or is in progress. We review here the current knowledge of Candida cell walls. We will also present a bioinformatics-based inventory of proteins either present in the cell walls, or involved in synthesis or modification of cell wall components, or in regulation of cell wall synthesis. These data will be integrated into a comprehensive picture of cell wall biology of Candida species.
14. Candida Cell Wall Proteins at the Host-Pathogen Interface
Margaret L. Zupancic and Brendan P. Cormack
During infection, the fungal cell surface, by its nature, is the first part of the cell to encounter the host. The fungal cell wall, therefore, is of vital importance in determining the nature and outcome of host-pathogen interactions. In different Candida species, proteins in the cell wall mediate a variety of cell-cell interactions important in virulence, including initial adherence to the host cell, uptake by certain mammalian cell types, and formation of biofilms. In addition, carbohydrate components of the cell wall serve as important modulators of the immune system. This chapter will examine the impact of Candida cell wall on overall virulence, focusing primarily on covalently attached cell wall proteins.
15. Strategic Analysis of Candida albicans Gene Function
Ryan L. Subaran and Aaron P. Mitchell
Between genetics and genomics, this is an exciting time to study fungal pathogens. We have employed a strategy based on mutant analysis of transcription factors to understand Candida albicans. Screening through a collection of homozygous insertion mutants, we have identified the transcription factors Bcr1 and Cas5 as master regulators of biofilm formation and the cell wall damage response, respectively. Analysis of their target genes has yielded insight into the pathways in which they are involved and uncovered new mechanistic information about biofilm formation and the cell wall damage response.
16. Genomic View on Antifungal Resistance Mechanisms Among Yeast and Fungal Pathogens
Most of the currently available antifungal agents are effective against common fungal pathogens, including Candida albicans and several other Candida species. Exposure of fungal pathogens to antifungal agents has different consequences (changes in gene expression, mobilization of signaling pathways, appearance of resistance). This review will summarize how genomic tools can contribute to characterize the response of fungal pathogens to antifungal agents and will give an update on the occurrence of resistance mechanisms across several yeast and fungal species.
17. A Post-genomic View of Candida-host Cell Interactions
Michael C. Lorenz
The release of the complete genome sequence of Candida albicans has enabled the development of genomic technologies in this important pathogen. These tools have been used to investigate the genome-wide responses of C. albicans to conditions directly relevant to pathogenesis in in vitro systems, including stress responses, morphogenesis, and interactions with host cells, in particular, to cells of the immune system. The picture emerging from these studies is one of complexity as seen in two ways. First, the responses can be extensive (r)C phagocytosis by macrophages or neutrophils alters expression of hundreds of genes. Secondly, the response programs are very specific. C. albicans responds to oxidative stresses by inducing only antioxidant genes; the broad environmental stress response network identified in Saccharomyces cerevisiae appears to be completely absent in C. albicans. Similarly, transcript profiles following phagocytosis by macrophages or neutrophils have only limited overlap, indicating that C. albicans can recognize the different immune cells. This chapter discusses these studies and the implications of these findings in the pathogenesis and biology of this organism.
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(EAN: 9781904455134 9781913652302 Subjects: [bacteriology] [microbiology] [medical microbiology] [molecular microbiology] [genomics] [mycology] )