Pathogenic Fungi: Insights in Molecular Biology | Book    

Publisher: Caister Academic Press
Edited by: ¹Gioconda San-Blas and ²Richard A. Calderone ¹Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela and ²Georgetown Univ Medical, Center Georgetown University, Washington DC, USA
Publication date: July 2008
ISBN: 978-1-904455-32-5
Price: GB £150 or US $310 (hardback).
Pages: 264

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Chapter 1 Gene Expression and Regulation
Carol Munro and Bernhard Hube
Fungal pathogens have to adapt to changing environments as infection develops in the host. Analysis of gene expression can provide valuable information to aid our understanding of how the fungus responds to a variety of specific interactions with the host. Gene expression studies can identify disease-associated fungal mechanisms and their regulation and this has the potential to facilitate the design of novel diagnostics and antifungal therapies. Here, we review the current gene expression technologies that have been applied to study fungal pathogens and summarise the transcriptional responses of a number of pathogenic fungi to different pathogenesis-related conditions such as interactions with macrophages, changing pH and temperature, morphogenesis and exposure to antifungal drugs or reactive nitrogen species. Some common responses emerge when different fungal species are subjected to the same stresses but there are interesting differences too, reflecting the different survival strategies that have emerged in divergent fungal species as they have evolved.

Chapter 2 Heterozygosity and Loss of Heterozygosity in Candida albicans
Germán Larriba and Richard A. Calderone
Although experiments in the early eighties demonstrated the natural auxotrophic heterozygosity of Candida albicans, an accurate estimate of the extent of that heterozygosity in terms of number, nature, and identification of polymorphisms had to wait until the genomic sequence of strain SC5314 and the subsequent elaboration of the diploid assembly was completed. The heterozygosity far exceeds that found in other polymorphic genomes such as human and Anopheles and is widespread among the clinical isolates. Non-synonymous single base polymorphisms (SNP) within a particular ORF result in two proteins that differ in one or several amino acids that may confer functional differences for each protein. This situation considerably increases the number of different proteins encoded by the genome. Furthermore, specific and/or differential expression of both alleles may be controlled by synonymous changes within the ORF or by polymorphisms in the regulatory regions. The high levels of heterozygosity in of a diploid organism with a predominantly clonal mode of propagation suggests that maintenance or even gain of this heterozygosity is essential to maintain genetic diversity within the species. The elucidation of the genetic mechanisms underlying these processes is essential to understand the biology of the organism. Recombination and chromosome loss may modify the levels of heterozygosity, and this may result in the acquisition of new properties, which include assimilation of normally unused sugars, resistance to antifungal compounds, ability to mate, modifications of virulence, etc. Once a certain level of heterozygosity has been reached and a haplotype has been established, mitotic recombination diversifies that haplotype within a particular locus or along the entire chromosome. A parasexual cycle may participate to increase diversity by shuffling alleles of genes that are located in the same or different pair of chromosomes.

Chapter 3 Regulatory Networks in the Host-fungal Pathogen Interactions
L. Fernandes, A.L. Bocca, A.M. Ribeiro, S.S. Silva, H.C. Paes, A.C. Amaral, V.L.P. Polez, N.F. Martins, C.M.A. Soares, and M.S.S. Felipe
The host innate immune response is critical for protection against infection. Macrophages and neutrophils mainly participate in this response, producing and releasing cytokines and chemokines. In addition, they present microbial antigens to lymphocytes, leading to the development of a highly specific immune response. Receptors are required for detection of microbial components that trigger signaling pathways to activate the host immune response. On the other hand, sensing and responding to the environment is required for fungal survival. Fungi have sophisticated and conserved signaling cascades to sense and respond to different types of stress including osmotic shock, temperature, oxidative or nitrosative damage. This review focuses on the main pathways that host cells use to recognize, interact and respond to fungal pathogens and also highlights the cascades that regulate environmental responses by the most studied human fungal pathogens.

Chapter 4 The Candida Immunome as a Mine for Clinical Biomarker Development for Invasive Candidiasis: From Biomarker Discovery to Assay Validation
Aída Pitarch, César Nombela and Concha Gil
Invasive candidiasis (IC) is a major cause of morbidity and mortality in intensive care, post-surgical, and cancer patients if not diagnosed and treated early. However, IC diagnosis at an early stage remains extremely difficult, leading to delayed therapy and ensuing poor prognosis. This clinical setting has motivated researchers to urgently search for prompt and accurate biomarkers for IC to direct appropriate diagnostic and therapeutic decision-making. Intriguingly, the characterization of molecular fingerprints of serum anti-Candida IgG antibodies in IC patients through the study of the Candida immunome (the subset of the Candida proteome targeted by the immune system) by classical immunoproteomics or serological proteome analysis (SERPA) provides a promising tool for discovering potential clinical biomarkers for IC. These may be used to improve early diagnosis, estimate patient outcome, predict therapy response, and/or monitor disease progression. Reminiscent of the development process of new therapeutic drugs, three sequential phases (discovery, validation and implementation) are also needed for the routine clinical use of a biomarker. Here we review the current status of these clinical biomarker development phases as applied to IC investigations using SERPA as an effective strategy to discover potential diagnostic, prognostic, predictive and monitoring biomarkers for IC.

Chapter 5 MAP Kinase Pathways in Pathogenic Fungi: Elements, Roles and Interactions
David M. Arana, Rebeca Alonso-Monge, Elvira Román, César Nombela and Jesús Pla
Signal transduction pathways are essential mechanisms used by all living cells to sense and transmit the information from external environment to the cell. For pathogenic fungi, they are essential mechanisms that transmit signals from a continuously host changing environment to the nucleus, where a response normally takes place. This adaptive response is crucial for the pathogen, as a failure to trigger it may result in elimination of the microbe from the host. Fungal signalling pathways are very diverse, and comprise MAPK pathways, cAMP-dependent protein kinase pathway (PKA pathway), calcium mediated signalling, Ras1 signalling and lipid mediated signalling among others, all of them closely interrelated. We aim to review here the main signalling pathways both in Candida albicans and Crypptococcus neoformans, two important human fungal pathogens, with special emphasis in the MAPK signalling and their relations with other adaptive mechanisms. The knowledge of such processes is important not only as a relevant aspect of modern biology but also as it may provides clues for the development of novel therapeutic strategies to fight fungal infections.

Chapter 6 Molecular Approaches to Target Drug Discovery in Human Pathogenic Fungi
Neeraj Chauhan and Richard Calderone
Anti-fungal drug discovery remains a major emphasis in research laboratories since current drugs can be toxic to the patient (amphotericin B) or less toxic but only inhibitory (triazoles) such that resistant strains are selected for during their use in patients. The high mortality and morbidity in patients, as for example, with invasive candidiasis in part is due to the inability to detect the organism. Consequently, empirical use of anti-fungals can offer coverage of the disease but again patients are at risk for the selection of drug resistant strains if triazoles are used. There are two approaches to new drug discovery. First, traditional methods utilize large compound libraries that can be tested against pathogens, gene-manipulated pathogens, or model fungi such as Saccharomyces cerevisiae. Hits are noted and then selected compounds are subjected to a serious scrutiny that includes identifying their specificity, toxicity, and redesigning the compound to increase its killing or reduce its toxicity. These facets are just part of the scheme that industry must fulfill to establish a new drug on the market. The development of molecular biology tools and the availability of whole genome sequences have provided a second recourse to drug discovery. Here, the emphasis has been placed upon the identification of essential genes; that insight is quite clear and easy to accept. If the pathogen requires a protein for its growth, then a drug that targets that protein has the same affect as the lack of that protein hopefully in the context of disease. Better yet, in the absence of that protein, the organism is inviable. In this review, methods will be discussed that provide leads in the race to find essential genes. Molecular biological approaches to this end are common to some fungal pathogens, but less studied in others. Thus, whether or not targets are common to many fungal pathogens, enabling the discovery of broad-based activities of select compounds is now partially addressed.

Chapter 7 Genome-wide Approaches to Understand Multi-drug Resistance in Pathogenic Fungi
Amelie Waldin, Nitnipa Soontorngun, Sarah MacPherson, Sadri Znaidi, Martine Raymond and Bernard Turcotte
A number of fungal species, such as Candida albicans, are human pathogens. Treatment with antifungal drugs quite often results in the appearance of resistant strains. Various mechanisms leading to resistance have been described. For example, a number of resistant clinical isolates overexpress genes encoding drug efflux pumps. Recent advances in molecular biology have allowed the study of the phenomenon of multi-drug resistance on a genome-wide scale. This chapter is aimed at first describing the use of DNA microarrays to study the expression profiling of pathogenic fungi. The second part of this review focuses on proteomic approaches used to determine variation of protein levels associated with the development of resistance to various antifungal drugs.

Chapter 8 New Approaches in the Diagnosis of Medically Relevant Mycoses: Fungal Identification by Molecular Techniques
Gioconda San-Blas and Gustavo Niño-Vega
Molecular diagnostic methods are currently being used for the early detection of many viral, bacterial, parasitic and fungal infections. Due to their high specificity and sensitivity, these methods will be inserted in the routine of the clinical laboratories to complement information provided by more conventional methods and above all, to help in the diagnosis of dubious cases. The design of specific probes, coupled to the Polymerase Chain Reaction (PCR) technique provides the required specificity and sensitivity to identify fungal species in a short time. Multicopy genes such as those of ribosomal origin are preferred by many researchers to achieve well defined results. However, because they may generate false positive results, other researchers have looked at single-copy genes of high specificity. Examples of both are presented in this review, applied to the identification of frequently found causative agents of systemic mycoses such as Candida albicans, Aspergillus fumigatus and other species within these genera, or agents of less frequent mycoses produced by Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, among others.

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(EAN: 9781904455325 Subjects: [microbiology] [medical microbiology] [molecular microbiology] [mycology])