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203 Publications visible to you, out of a total of 203

Abstract (Expand)

Fungi produce a multitude of low-molecular-mass compounds known as secondary metabolites, which have roles in a range of cellular processes such as transcription, development and intercellular communication. In addition, many of these compounds now have important applications, for instance, as antibiotics or immunosuppressants. Genome mining efforts indicate that the capability of fungi to produce secondary metabolites has been substantially underestimated because many of the fungal secondary metabolite biosynthesis gene clusters are silent under standard cultivation conditions. In this Review, I describe our current understanding of the regulatory elements that modulate the transcription of genes involved in secondary metabolism. I also discuss how an improved knowledge of these regulatory elements will ultimately lead to a better understanding of the physiological and ecological functions of these important compounds and will pave the way for a novel avenue to drug discovery through targeted activation of silent gene clusters.

Author: Axel A Brakhage

Date Published: 26th Nov 2012

Publication Type: Not specified

Abstract

ABSTRACT:

Authors: Sebastian Müller, Clara Baldin, Marco Groth, Reinhard Guthke, Olaf Kniemeyer, Axel A Brakhage, Vito Valiante

Date Published: 2nd Oct 2012

Publication Type: Not specified

Abstract (Expand)

The ability to adapt to diverse micro-environmental challenges encountered within a host is of pivotal importance to the opportunistic fungal pathogen Candida albicans. We have quantified C. albicans and M. musculus gene expression dynamics during phagocytosis by dendritic cells in a genome-wide, time-resolved analysis using simultaneous RNA-seq. A robust network inference map was generated from this dataset using NetGenerator, predicting novel interactions between the host and the pathogen. We experimentally verified predicted interdependent sub-networks comprising Hap3 in C. albicans, and Ptx3 and Mta2 in M. musculus. Remarkably, binding of recombinant Ptx3 to the C. albicans cell wall was found to regulate the expression of fungal Hap3 target genes as predicted by the network inference model. Pre-incubation of C. albicans with recombinant Ptx3 significantly altered the expression of Mta2 target cytokines such as IL-2 and IL-4 in a Hap3-dependent manner, further suggesting a role for Mta2 in host-pathogen interplay as predicted in the network inference model. We propose an integrated model for the functionality of these sub-networks during fungal invasion of immune cells, according to which binding of Ptx3 to the C. albicans cell wall induces remodeling via fungal Hap3 target genes, thereby altering the immune response to the pathogen. We show the applicability of network inference to predict interactions between host-pathogen pairs, demonstrating the usefulness of this systems biology approach to decipher mechanisms of microbial pathogenesis.

Authors: L. Tierney, , S. Muller, S. Brunke, J. C. Molina, , U. Schock, , K. Kuchler

Date Published: 12th Mar 2012

Publication Type: Not specified

Abstract (Expand)

BACKGROUND: In System Biology, iterations of wet-lab experiments followed by modelling approaches and model-inspired experiments describe a cyclic workflow. This approach is especially useful for the inference of gene regulatory networks based on high-throughput gene expression data. Experiments can verify or falsify the predicted interactions allowing further refinement of the network model. Aspergillus fumigatus is a major human fungal pathogen. One important virulence trait is its ability to gain sufficient amounts of iron during infection process. Even though some regulatory interactions are known, we are still far from a complete understanding of the way iron homeostasis is regulated. RESULTS: In this study, we make use of a reverse engineering strategy to infer a regulatory network controlling iron homeostasis in A. fumigatus. The inference approach utilizes the temporal change in expression data after a change from iron depleted to iron replete conditions. The modelling strategy is based on a set of linear differential equations and offers the possibility to integrate known regulatory interactions as prior knowledge. Moreover, it makes use of important selection criteria, such as sparseness and robustness. By compiling a list of known regulatory interactions for iron homeostasis in A. fumigatus and softly integrating them during network inference, we are able to predict new interactions between transcription factors and target genes. The proposed activation of the gene expression of hapX by the transcriptional regulator SrbA constitutes a so far unknown way of regulating iron homeostasis based on the amount of metabolically available iron. This interaction has been verified by Northern blots in a recent experimental study. In order to improve the reliability of the predicted network, the results of this experimental study have been added to the set of prior knowledge. The final network includes three SrbA target genes. Based on motif searching within the regulatory regions of these genes, we identify potential DNA-binding sites for SrbA. Our wet-lab experiments demonstrate high-affinity binding capacity of SrbA to the promoters of hapX, hemA and srbA. CONCLUSIONS: This study presents an application of the typical Systems Biology circle and is based on cooperation between wet-lab experimentalists and in silico modellers. The results underline that using prior knowledge during network inference helps to predict biologically important interactions. Together with the experimental results, we indicate a novel iron homeostasis regulating system sensing the amount of metabolically available iron and identify the binding site of iron-related SrbA target genes. It will be of high interest to study whether these regulatory interactions are also important for close relatives of A. fumigatus and other pathogenic fungi, such as Candida albicans.

Authors: , P. Hortschansky, E. Fazius, , , H. Haas

Date Published: 19th Jan 2012

Publication Type: Not specified

Abstract (Expand)

Non-invasive imaging techniques in microbial disease models have delivered valuable insights in the intimate pathogen-host interplay during infection. Here we describe evaluation and validation of a transgenic bioluminescence reporter strain of the human-pathogenic mold Aspergillus fumigatus, one of the main fungal pathogens affecting immunocompromised individuals. Expression and surface display of the Gaussia princeps luciferase allowed sensitive and rapid detection of luminescence emitted from this strain after substrate addition, with photon fluxes strongly correlating to the amounts of fungal conidia or germlings. The reporter strain allowed spatio-temporal monitoring of infection in a cutaneous model of aspergillosis, where neutropenic mice maintained the fungal burden while immunocompetent ones were able to clear it entirely. Most importantly, antifungal therapy could be followed in this type of disease model making use of the bioluminescent A. fumigatus strain. In conclusion, combining sensitivity of the Gaussia luciferase with a surface display expression system in the fungal host allows longitudinal infection studies on cutaneous forms of aspergillosis, providing perspective on drug screening approaches at high-throughput.

Authors: Stefanie Donat, Mike Hasenberg, Tina Schäfer, Knut Ohlsen, Matthias Gunzer, Hermann Einsele, Jürgen Löffler, Andreas Beilhack, Sven Krappmann

Date Published: 2012

Publication Type: Not specified

Abstract (Expand)

FungiDB (http://FungiDB.org) is a functional genomic resource for pan-fungal genomes that was developed in partnership with the Eukaryotic Pathogen Bioinformatic resource center (http://EuPathDB.org). FungiDB uses the same infrastructure and user interface as EuPathDB, which allows for sophisticated and integrated searches to be performed using an intuitive graphical system. The current release of FungiDB contains genome sequence and annotation from 18 species spanning several fungal classes, including the Ascomycota classes, Eurotiomycetes, Sordariomycetes, Saccharomycetes and the Basidiomycota orders, Pucciniomycetes and Tremellomycetes, and the basal 'Zygomycete' lineage Mucormycotina. Additionally, FungiDB contains cell cycle microarray data, hyphal growth RNA-sequence data and yeast two hybrid interaction data. The underlying genomic sequence and annotation combined with functional data, additional data from the FungiDB standard analysis pipeline and the ability to leverage orthology provides a powerful resource for in silico experimentation.

Authors: Jason E Stajich, Todd Harris, Brian P Brunk, John Brestelli, Steve Fischer, Omar S Harb, Jessica C Kissinger, Wei Li, Vishal Nayak, Deborah F Pinney, Chris J Stoeckert, David S Roos

Date Published: 7th Nov 2011

Publication Type: Not specified

Abstract (Expand)

FungiFun assigns functional annotations to fungal genes or proteins and performs gene set enrichment analysis. Based on three different classification methods (FunCat, GO and KEGG), FungiFun categorizes genes and proteins for several fungal species on different levels of annotation detail. It is web-based and accessible to users without any programming skills. FungiFun is the first tool offering gene set enrichment analysis including the FunCat categorization. Two biological datasets for Aspergillus fumigatus and Candida albicans were analyzed using FungiFun, providing an overview of the usage and functions of the tool. FungiFun is freely accessible at https://www.omnifung.hki-jena.de/FungiFun/.

Authors: S. Priebe, , D. Albrecht, , A. A. Brakhage

Date Published: 10th Nov 2010

Publication Type: Not specified

Abstract

Not specified

Authors: A. Schmoldt, H. F. Benthe, G. Haberland

Date Published: 1st Sep 1975

Publication Type: Not specified

Abstract (Expand)

Candida albicans is an important human opportunistic fungal pathogen which is frequently found as part of the normal human microbiota. It is well accepted that the fungus interacts with other components of the resident microbiota and that this impacts the commensal or pathogenic outcome of C. albicans colonization. Different types of interactions, including synergism or antagonism, contribute to a complex balance between the multitude of different species. Mixed biofilms of C. albicans and streptococci are a well-studied example of a mutualistic interaction often potentiating the virulence of the individual members. In contrast, other bacteria like lactobacilli are known to antagonize C. albicans, and research has just started elucidating the mechanisms behind these interactions. This scenario is even more complicated by a third player, the host. This review focuses on interactions between C. albicans and gram-positive bacteria whose investigation will without doubt ultimately help understanding C. albicans infections.

Editor:

Date Published: No date defined

Publication Type: Not specified

Abstract (Expand)

The identification of novel transcription factors associated with antifungal response may allow the discovery of fungus-specific targets for new therapeutic strategies. A collection of 241 Candida albicans transcriptional regulator mutants was screened for altered susceptibility to fluconazole, caspofungin, amphotericin B, and 5-fluorocytosine. Thirteen of these mutants not yet identified in terms of their role in antifungal response were further investigated, and the function of one of them, a mutant of orf19.6102 (RCA1), was characterized by transcriptome analysis. Strand-specific RNA sequencing and phenotypic tests assigned Rca1 as the regulator of hyphal formation through the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway and the transcription factor Efg1, but also probably through its interaction with a transcriptional repressor, most likely Tup1. The mechanisms responsible for the high level of resistance to caspofungin and fluconazole observed resulting from RCA1 deletion were investigated. From our observations, we propose that caspofungin resistance was the consequence of the deregulation of cell wall gene expression and that fluconazole resistance was linked to the modulation of the cAMP/PKA signaling pathway activity. In conclusion, our large-scale screening of a C. albicans transcription factor mutant collection allowed the identification of new effectors of the response to antifungals. The functional characterization of Rca1 assigned this transcription factor and its downstream targets as promising candidates for the development of new therapeutic strategies, as Rca1 influences host sensing, hyphal development, and antifungal response.

Authors: P. Vandeputte, S. Pradervand, F. Ischer, A. T. Coste, S. Ferrari, K. Harshman, D. Sanglard

Date Published: No date defined

Publication Type: Not specified

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