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Survival Strategies of Pathogenic Candida Species in Human Blood Show Independent and Specific Adaptations.
INF, B3 (E), C1, C3

Abstract (Expand)

Only four species, Candida albicans, C. glabrata, C. parapsilosis, and C. tropicalis, together account for about 90% of all Candida bloodstream infections and are among the most common causes of invasive … fungal infections of humans. However, virulence potential varies among these species, and the phylogenetic tree reveals that their pathogenicity may have emerged several times independently during evolution. We therefore tested these four species in a human whole-blood infection model to determine, via comprehensive dual-species RNA-sequencing analyses, which fungal infection strategies are conserved and which are recent evolutionary developments. The ex vivo infection progressed from initial immune cell interactions to nearly complete killing of all fungal cells. During the course of infection, we characterized important parameters of pathogen-host interactions, such as fungal survival, types of interacting immune cells, and cytokine release. On the transcriptional level, we obtained a predominantly uniform and species-independent human response governed by a strong upregulation of proinflammatory processes, which was downregulated at later time points after most of the fungal cells were killed. In stark contrast, we observed that the different fungal species pursued predominantly individual strategies and showed significantly different global transcriptome patterns. Among other findings, our functional analyses revealed that the fungal species relied on different metabolic pathways and virulence factors to survive the host-imposed stress. These data show that adaptation of Candida species as a response to the host is not a phylogenetic trait, but rather has likely evolved independently as a prerequisite to cause human infections.IMPORTANCE To ensure their survival, pathogens have to adapt immediately to new environments in their hosts, for example, during the transition from the gut to the bloodstream. Here, we investigated the basis of this adaptation in a group of fungal species which are among the most common causes of hospital-acquired infections, the Candida species. On the basis of a human whole-blood infection model, we studied which genes and processes are active over the course of an infection in both the host and four different Candida pathogens. Remarkably, we found that, while the human host response during the early phase of infection is predominantly uniform, the pathogens pursue largely individual strategies and each one regulates genes involved in largely disparate processes in the blood. Our results reveal that C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis all have developed individual strategies for survival in the host. This indicates that their pathogenicity in humans has evolved several times independently and that genes which are central for survival in the host for one species may be irrelevant in another.

Authors: P. Kammer, S. McNamara, Thomas Wolf, Theresia Conrad, Stefanie Allert, F. Gerwien, Kerstin Hünniger, Oliver Kurzai, Reinhard Guthke, Bernhard Hube, Jörg Linde, S. Brunke

Date Published: 6th Oct 2020

Journal: mBio

Specific and Novel microRNAs Are Regulated as Response to Fungal Infection in Human Dendritic Cells.
INF, A2, B3 (E), C3

Abstract (Expand)

Within the last two decades, the incidence of invasive fungal infections has been significantly increased. They are characterized by high mortality rates and are often caused by Candida albicans and … Aspergillus fumigatus. The increasing number of infections underlines the necessity for additional anti-fungal therapies, which require extended knowledge of gene regulations during fungal infection. MicroRNAs are regulators of important cellular processes, including the immune response. By analyzing their regulation and impact on target genes, novel therapeutic and diagnostic approaches may be developed. Here, we examine the role of microRNAs in human dendritic cells during fungal infection. Dendritic cells represent the bridge between the innate and the adaptive immune systems. Therefore, analysis of gene regulation of dendritic cells is of particular significance. By applying next-generation sequencing of small RNAs, we quantify microRNA expression in monocyte-derived dendritic cells after 6 and 12 h of infection with C. albicans and A. fumigatus as well as treatment with lipopolysaccharides (LPS). We identified 26 microRNAs that are differentially regulated after infection by the fungi or LPS. Three and five of them are specific for fungal infections after 6 and 12 h, respectively. We further validated interactions of miR-132-5p and miR-212-5p with immunological relevant target genes, such as FKBP1B, KLF4, and SPN, on both RNA and protein level. Our results indicate that these microRNAs fine-tune the expression of immune-related target genes during fungal infection. Beyond that, we identified previously undiscovered microRNAs. We validated three novel microRNAs via qRT-PCR. A comparison with known microRNAs revealed possible relations with the miR-378 family and miR-1260a/b for two of them, while the third one features a unique sequence with no resemblance to known microRNAs. In summary, this study analyzes the effect of known microRNAs in dendritic cells during fungal infections and proposes novel microRNAs that could be experimentally verified.

Authors: Andreas Dix, K. Czakai, I. Leonhardt, K. Schaferhoff, M. Bonin, Reinhard Guthke, Hermann Einsele, Oliver Kurzai, Jürgen Löffler, Jörg Linde

Date Published: 11th Mar 2017

Journal: Front Microbiol

Use of systems biology to decipher host microbial interactions and predict pathological consequences
FungiNet B - Bioinformatics projects, INF, B3 (E)

Abstract (Expand)

In systems biology, researchers aim to understand complex biological systems as a whole, which is often achieved by mathematical modelling and the analyses of high-throughput data. In this review, we … give an overview of medical applications of systems biology approaches with special focus on host-pathogen interactions. After introducing general ideas of systems biology, we focus on (1) the detection of putative biomarkers for improved diagnosis and support of therapeutic decisions; (2) network modelling for the identification of regulatory interactions between cellular molecules to reveal putative drug targets; (3) module discovery for the detection of phenotype-specific modules in molecular interaction networks. Biomarker detection applies supervised machine learning methods utilising high-throughput data (e.g. SNP detection, RNA-seq, proteomics) and clinical data. We demonstrate structural analysis of molecular networks, especially by identification of disease modules as novel strategy, and discuss possible applications to host-pathogen interactions. Pioneering work was done to predict molecular host-pathogen interactions networks based on dual RNA-seq data. However, currently this network modelling is restricted to a small number of genes. With increasing number and quality of databases and data repositories, also the prediction of large-scale networks will be feasible that can used for multi-dimensional diagnosis and decision support for prevention and therapy of diseases. Finally, we outline further perspective issues such as support of personalised medicine with high-throughput data and generation of multi-scale host-pathogen interaction models.

Authors: Andreas Dix, S. Vlaic, Reinhard Guthke, Jörg Linde

Date Published: 27th Apr 2016

Journal: Clin Microbiol Infect

Data-based Reconstruction of Gene Regulatory Networks of Fungal Pathogens
FungiNet B - Bioinformatics projects, INF, B3 (E)

Abstract (Expand)

In the emerging field of systems biology of fungal infection, one of the central roles belongs to the modeling of gene regulatory networks (GRNs). Utilizing omics-data, GRNs can be predicted by … mathematical modeling. Here, we review current advances of data-based reconstruction of both small-scale and large-scale GRNs for human pathogenic fungi. The advantage of large-scale genome-wide modeling is the possibility to predict central (hub) genes and thereby indicate potential biomarkers and drug targets. In contrast, small-scale GRN models provide hypotheses on the mode of gene regulatory interactions, which have to be validated experimentally. Due to the lack of sufficient quantity and quality of both experimental data and prior knowledge about regulator-target gene relations, the genome-wide modeling still remains problematic for fungal pathogens. While a first genome-wide GRN model has already been published for Candida albicans, the feasibility of such modeling for Aspergillus fumigatus is evaluated in the present article. Based on this evaluation, opinions are drawn on future directions of GRN modeling of fungal pathogens. The crucial point of genome-wide GRN modeling is the experimental evidence, both used for inferring the networks (omics 'first-hand' data as well as literature data used as prior knowledge) and for validation and evaluation of the inferred network models.

Authors: Reinhard Guthke, S. Gerber, Theresia Conrad, S. Vlaic, S. Durmus, T. Cakir, F. E. Sevilgen, Ekaterina Shelest, Jörg Linde

Date Published: 22nd Apr 2016

Journal: Front Microbiol

Genome-Wide Expression Profiling Reveals S100B as Biomarker for Invasive Aspergillosis
FungiNet A - Aspergillus projects, FungiNet B - Bioinformatics projects, INF, B3 (E)

Abstract (Expand)

Invasive aspergillosis (IA) is a devastating opportunistic infection and its treatment constitutes a considerable burden for the health care system. Immunocompromised patients are at an increased risk … for IA, which is mainly caused by the species Aspergillus fumigatus. An early and reliable diagnosis is required to initiate the appropriate antifungal therapy. However, diagnostic sensitivity and accuracy still needs to be improved, which can be achieved at least partly by the definition of new biomarkers. Besides the direct detection of the pathogen by the current diagnostic methods, the analysis of the host response is a promising strategy toward this aim. Following this approach, we sought to identify new biomarkers for IA. For this purpose, we analyzed gene expression profiles of hematological patients and compared profiles of patients suffering from IA with non-IA patients. Based on microarray data, we applied a comprehensive feature selection using a random forest classifier. We identified the transcript coding for the S100 calcium-binding protein B (S100B) as a potential new biomarker for the diagnosis of IA. Considering the expression of this gene, we were able to classify samples from patients with IA with 82.3% sensitivity and 74.6% specificity. Moreover, we validated the expression of S100B in a real-time reverse transcription polymerase chain reaction (RT-PCR) assay and we also found a down-regulation of S100B in A. fumigatus stimulated DCs. An influence on the IL1B and CXCL1 downstream levels was demonstrated by this S100B knockdown. In conclusion, this study covers an effective feature selection revealing a key regulator of the human immune response during IA. S100B may represent an additional diagnostic marker that in combination with the established techniques may improve the accuracy of IA diagnosis.

Authors: Andreas Dix, K. Czakai, J. Springer, M. Fliesser, M. Bonin, Reinhard Guthke, A. L. Schmitt, Hermann Einsele, Jörg Linde, Jürgen Löffler

Date Published: 21st Mar 2016

Journal: Front Microbiol

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

Editorial: Computational Systems Biology of Pathogen-Host Interactions
FungiNet B - Bioinformatics projects, INF, B3 (E)

Abstract

Not specified

Authors: S. Durmus, T. Cakir, Reinhard Guthke

Date Published: 4th Feb 2016

Journal: Front Microbiol

Hitting the caspofungin salvage pathway of human-pathogenic fungi with the novel lasso peptide humidimycin (MDN-0010)
FungiNet A - Aspergillus projects, B3 (E)

Abstract (Expand)

Fungal infections have increased dramatically in the last 2 decades, and fighting infectious diseases requires innovative approaches such as the combination of two drugs acting on different targets or … even targeting a salvage pathway of one of the drugs. The fungal cell wall biosynthesis is inhibited by the clinically used antifungal drug caspofungin. This antifungal activity has been found to be potentiated by humidimycin, a new natural product identified from the screening of a collection of 20,000 microbial extracts, which has no major effect when used alone. An analysis of transcriptomes and selected Aspergillus fumigatus mutants indicated that humidimycin affects the high osmolarity glycerol response pathway. By combining humidimycin and caspofungin, a strong increase in caspofungin efficacy was achieved, demonstrating that targeting different signaling pathways provides an excellent basis to develop novel anti-infective strategies.

Authors: Vito Valiante, M. C. Monteiro, J. Martin, R. Altwasser, N. El Aouad, I. Gonzalez, Olaf Kniemeyer, E. Mellado, S. Palomo, N. de Pedro, I. Perez-Victoria, J. R. Tormo, F. Vicente, F. Reyes, O. Genilloud, Axel Brakhage

Date Published: 8th Jun 2015

Journal: Antimicrob Agents Chemother

Data- and knowledge-based modeling of gene regulatory networks: an update
FungiNet B - Bioinformatics projects, INF, B3 (E)

Abstract (Expand)

Gene regulatory network inference is a systems biology approach which predicts interactions between genes with the help of high-throughput data. In this review, we present current and updated network … inference methods focusing on novel techniques for data acquisition, network inference assessment, network inference for interacting species and the integration of prior knowledge. After the advance of Next-Generation-Sequencing of cDNAs derived from RNA samples (RNA-Seq) we discuss in detail its application to network inference. Furthermore, we present progress for large-scale or even full-genomic network inference as well as for small-scale condensed network inference and review advances in the evaluation of network inference methods by crowdsourcing. Finally, we reflect the current availability of data and prior knowledge sources and give an outlook for the inference of gene regulatory networks that reflect interacting species, in particular pathogen-host interactions.

Authors: Jörg Linde, Sylvie Schulze, S. G. Henkel, Reinhard Guthke

Date Published: 2nd Mar 2015

Journal: EXCLI J

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