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Flotillin-Dependent Membrane Microdomains Are Required for Functional Phagolysosomes against Fungal Infections.
FungiNet A - Aspergillus projects, B4

Abstract (Expand)

Lipid rafts form signaling platforms on biological membranes with incompletely characterized role in immune response to infection. Here we report that lipid-raft microdomains are essential components … of phagolysosomal membranes of macrophages and depend on flotillins. Genetic deletion of flotillins demonstrates that the assembly of both major defense complexes vATPase and NADPH oxidase requires membrane microdomains. Furthermore, we describe a virulence mechanism leading to dysregulation of membrane microdomains by melanized wild-type conidia of the important human-pathogenic fungus Aspergillus fumigatus resulting in reduced phagolysosomal acidification. We show that phagolysosomes with ingested melanized conidia contain a reduced amount of free Ca(2+) ions and that inhibition of Ca(2+)-dependent calmodulin activity led to reduced lipid-raft formation. We identify a single-nucleotide polymorphism in the human FLOT1 gene resulting in heightened susceptibility for invasive aspergillosis in hematopoietic stem cell transplant recipients. Collectively, flotillin-dependent microdomains on the phagolysosomal membrane play an essential role in protective antifungal immunity.

Authors: F. Schmidt, A. Thywissen, M. Goldmann, C. Cunha, Z. Cseresnyes, H. Schmidt, M. Rafiq, S. Galiani, M. H. Graler, G. Chamilos, J. F. Lacerda, A. Jr Campos, C. Eggeling, Marc Thilo Figge, Thorsten Heinekamp, S. G. Filler, A. Carvalho, Axel Brakhage

Date Published: 18th Aug 2020

Journal: Cell Rep

Functional surface proteomic profiling reveals the host heat-shock protein A8 as a mediator of Lichtheimia corymbifera recognition by murine alveolar macrophages.
A1, A5, B4, Z2, A6

Abstract (Expand)

Mucormycosis is an emergent, fatal fungal infection of humans and warm-blooded animals caused by species of the order Mucorales. Immune cells of the innate immune system serve as the first line of … defence against inhaled spores. Alveolar macrophages were challenged with the mucoralean fungus Lichtheimia corymbifera and subjected to biotinylation and streptavidin enrichment procedures followed by LC-MS/MS analyses. A total of 28 host proteins enriched for binding to macrophage-L. corymbifera interaction. Among those, the HSP70-family protein Hspa8 was found to be predominantly responsive to living and heat-killed spores of a virulent and an attenuated strain of L. corymbifera. Confocal scanning laser microscopy of infected macrophages revealed colocalization of Hspa8 with phagocytosed spores of L. corymbifera. The amount of detectable Hspa8 was dependent on the multiplicity of infection. Incubation of alveolar macrophages with an anti-Hspa8 antibody prior to infection reduced their capability to phagocytose spores of L. corymbifera. In contrast, anti-Hspa8 antibodies did not abrogate the phagocytosis of Aspergillus fumigatus conidia by macrophages. These results suggest an important contribution of the heat-shock family protein Hspa8 in the recognition of spores of the mucoralean fungus L. corymbifera by host alveolar macrophages and define a potential immunomodulatory therapeutic target.

Authors: M. I. A. Hassan, J. M. Kruse, Thomas Krüger, H. M. Dahse, Z. Cseresnyes, M. G. Blango, Hortense Slevogt, F. Horhold, V. Ast, R. Konig, Marc Thilo Figge, Olaf Kniemeyer, Axel Brakhage, Kerstin Voigt

Date Published: 26th Jun 2020

Journal: Environ Microbiol

Factor H Binds to Extracellular DNA Traps Released from Human Blood Monocytes in Response to Candida albicans.
C4 (E)

Abstract (Expand)

Upon systemic infection with human pathogenic yeast Candida albicans (C. albicans), human monocytes and polymorph nuclear neutrophilic granulocytes are the first immune cells to respond and come into … contact with C. albicans. Monocytes exert immediate candidacidal activity and inhibit germination, mediate phagocytosis, and kill fungal cells. Here, we show that human monocytes spontaneously respond to C. albicans cells via phagocytosis, decondensation of nuclear DNA, and release of this decondensed DNA in the form of extracellular traps (called monocytic extracellular traps: MoETs). Both subtypes of monocytes (CD14(++)CD16(-)/CD14(+)CD16(+)) formed MoETs within the first hours upon contact with C. albicans. MoETs were characterized by the presence of citrullinated histone, myeloperoxidase, lactoferrin, and elastase. MoETs were also formed in response to Staphylococcus aureus and Escherichia coli, indicating a general reaction of monocytes to infectious microbes. MoET induction differs from extracellular trap formation in macrophages as MoETs are not triggered by simvastatin, an inhibitor of cholesterol synthesis and inducer of extracellular traps in macrophages. Extracellular traps from both monocytes and neutrophils activate complement and C3b is deposited. However, factor H (FH) binds via C3b to the extracellular DNA, mediates cofactor activity, and inhibits the induction of the inflammatory cytokine interleukin-1 beta in monocytes. Altogether, the results show that human monocytes release extracellular DNA traps in response to C. albicans and that these traps finally bind FH via C3b to presumably support clearance without further inflammation.

Authors: Luke Donald Halder, M. A. Abdelfatah, E. A. Jo, Ilse Jacobsen, M. Westermann, Niklas Beyersdorf, S. Lorkowski, Peter Zipfel, Christine Skerka

Date Published: 31st Jan 2017

Journal: Front Immunol

Facing the challenges of multiscale modelling of bacterial and fungal pathogen-host interactions
FungiNet B - Bioinformatics projects, INF, B3 (E)

Abstract (Expand)

Recent and rapidly evolving progress on high-throughput measurement techniques and computational performance has led to the emergence of new disciplines, such as systems medicine and translational … systems biology. At the core of these disciplines lies the desire to produce multiscale models: mathematical models that integrate multiple scales of biological organization, ranging from molecular, cellular and tissue models to organ, whole-organism and population scale models. Using such models, hypotheses can systematically be tested. In this review, we present state-of-the-art multiscale modelling of bacterial and fungal infections, considering both the pathogen and host as well as their interaction. Multiscale modelling of the interactions of bacteria, especially Mycobacterium tuberculosis, with the human host is quite advanced. In contrast, models for fungal infections are still in their infancy, in particular regarding infections with the most important human pathogenic fungi, Candida albicans and Aspergillus fumigatus. We reflect on the current availability of computational approaches for multiscale modelling of host-pathogen interactions and point out current challenges. Finally, we provide an outlook for future requirements of multiscale modelling.

Authors: J. Schleicher, Theresia Conrad, M. Gustafsson, G. Cedersund, Reinhard Guthke, Jörg Linde

Date Published: 10th Feb 2016

Journal: Brief Funct Genomics

Function and Regulation of Cph2 in Candida albicans.
FungiNet C - Candida projects

Abstract (Expand)

Candida albicans is associated with humans as both a harmless commensal organism and a pathogen. Cph2 is a transcription factor whose DNA binding domain is similar to that of mammalian sterol response … element binding proteins (SREBPs). SREBPs are master regulators of cellular cholesterol levels and are highly conserved from fungi to mammals. However, ergosterol biosynthesis is regulated by the zinc finger transcription factor Upc2 in C. albicans and several other yeasts. Cph2 is not necessary for ergosterol biosynthesis but is important for colonization in the murine gastrointestinal (GI) tract. Here we demonstrate that Cph2 is a membrane-associated transcription factor that is processed to release the N-terminal DNA binding domain like SREBPs, but its cleavage is not regulated by cellular levels of ergosterol or oxygen. Chromatin immunoprecipitation sequencing (ChIP-seq) shows that Cph2 binds to the promoters of HMS1 and other components of the regulatory circuit for GI tract colonization. In addition, 50% of Cph2 targets are also bound by Hms1 and other factors of the regulatory circuit. Several common targets function at the head of the glycolysis pathway. Thus, Cph2 is an integral part of the regulatory circuit for GI colonization that regulates glycolytic flux. Transcriptome sequencing (RNA-seq) shows a significant overlap in genes differentially regulated by Cph2 and hypoxia, and Cph2 is important for optimal expression of some hypoxia-responsive genes in glycolysis and the citric acid cycle. We suggest that Cph2 and Upc2 regulate hypoxia-responsive expression in different pathways, consistent with a synthetic lethal defect of the cph2 upc2 double mutant in hypoxia.

Authors: S. Lane, P. Di Lena, K. Tormanen, P. Baldi, H. Liu

Date Published: 6th Sep 2015

Journal: Eukaryot Cell

Footprints of optimal protein assembly strategies in the operonic structure of prokaryotes
FungiNet total, B2

Abstract (Expand)

In this work, we investigate optimality principles behind synthesis strategies for protein complexes using a dynamic optimization approach. We show that the cellular capacity of protein synthesis has … a strong influence on optimal synthesis strategies reaching from a simultaneous to a sequential synthesis of the subunits of a protein complex. Sequential synthesis is preferred if protein synthesis is strongly limited, whereas a simultaneous synthesis is optimal in situations with a high protein synthesis capacity. We confirm the predictions of our optimization approach through the analysis of the operonic organization of protein complexes in several hundred prokaryotes. Thereby, we are able to show that cellular protein synthesis capacity is a driving force in the dissolution of operons comprising the subunits of a protein complex. Thus, we also provide a tested hypothesis explaining why the subunits of many prokaryotic protein complexes are distributed across several operons despite the presumably less precise co-regulation.

Authors: Jan Ewald, M. Kotzing, M. Bartl, Christoph Kaleta

Date Published: 1st May 2015

Journal: Metabolites

Footprints of optimal protein assembly strategies in the operonic structure of prokaryotes
FungiNet B - Bioinformatics projects

Abstract (Expand)

In this work, we investigate optimality principles behind synthesis strategies for protein complexes using a dynamic optimization approach. We show that the cellular capacity of protein synthesis has … a strong influence on optimal synthesis strategies reaching from a simultaneous to a sequential synthesis of the subunits of a protein complex. Sequential synthesis is preferred if protein synthesis is strongly limited, whereas a simultaneous synthesis is optimal in situations with a high protein synthesis capacity. We confirm the predictions of our optimization approach through the analysis of the operonic organization of protein complexes in several hundred prokaryotes. Thereby, we are able to show that cellular protein synthesis capacity is a driving force in the dissolution of operons comprising the subunits of a protein complex. Thus, we also provide a tested hypothesis explaining why the subunits of many prokaryotic protein complexes are distributed across several operons despite the presumably less precise co-regulation.

Authors: J. Ewald, M. Kotzing, M. Bartl, Christoph Kaleta

Date Published: 1st May 2015

Journal: Metabolites

Factors supporting cysteine tolerance and sulfite production in Candida albicans
FungiNet C - Candida projects

Abstract (Expand)

The amino acid cysteine has long been known to be toxic at elevated levels for bacteria, fungi, and humans. However, mechanisms of cysteine tolerance in microbes remain largely obscure. Here we show … that the human pathogenic yeast Candida albicans excretes sulfite when confronted with increasing cysteine concentrations. Mutant construction and phenotypic analysis revealed that sulfite formation from cysteine in C. albicans relies on cysteine dioxygenase Cdg1, an enzyme with similar functions in humans. Environmental cysteine induced not only the expression of the CDG1 gene in C. albicans, but also the expression of SSU1, encoding a putative sulfite efflux pump. Accordingly, the deletion of SSU1 resulted in enhanced sensitivity of the fungal cells to both cysteine and sulfite. To study the regulation of sulfite/cysteine tolerance in more detail, we screened a C. albicans library of transcription factor mutants in the presence of sulfite. This approach and subsequent independent mutant analysis identified the zinc cluster transcription factor Zcf2 to govern sulfite/cysteine tolerance, as well as cysteine-inducible SSU1 and CDG1 gene expression. cdg1Delta and ssu1Delta mutants displayed reduced hypha formation in the presence of cysteine, indicating a possible role of the newly proposed mechanisms of cysteine tolerance and sulfite secretion in the pathogenicity of C. albicans. Moreover, cdg1Delta mutants induced delayed mortality in a mouse model of disseminated infection. Since sulfite is toxic and a potent reducing agent, its production by C. albicans suggests diverse roles during host adaptation and pathogenicity.

Authors: F. Hennicke, M. Grumbt, U. Lermann, N. Ueberschaar, K. Palige, B. Bottcher, Ilse Jacobsen, C. Staib, J. Morschhauser, M. Monod, Bernhard Hube, C. Hertweck, P. Staib

Date Published: 15th Feb 2013

Journal: Eukaryot Cell

FungiDB: an integrated functional genomics database for fungi
FungiNet B - Bioinformatics projects

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

Journal: Nucleic Acids Res.

FungiFun: a web-based application for functional categorization of fungal genes and proteins
INF

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, Jörg Linde, D. Albrecht, Reinhard Guthke, A. A. Brakhage

Date Published: 10th Nov 2010

Journal: Fungal Genet Biol

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