Theresia Conrad

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About Theresia Conrad:

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SEEK ID: https://funginet.hki-jena.de/people/101

Location: Germany

ORCID: Not specified

Joined: 10th May 2016

Expertise: Not specified

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Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

The yeast Candida albicans and the filamentous fungus Aspergillus fumigatus are by far the most important causes of life-threatening invasive mycoses in Europe. Despite the increasing incidence of these infections, the current diagnosis is still difficult and often too late, and options for therapies are limited. Moreover, A. fumigatus and C. albicans have developed multiple sophisticated, specific and unique pathogenicity mechanisms. Many of these mechanisms are not well understood. Research on ...

Projects: FungiNet total, FungiNet A - Aspergillus projects, FungiNet B - Bioinformatics projects, FungiNet C - Candida projects, INF, A1, A2, A3, A4 (E), A5, B1, B2, B3 (E), B4, C1, C2, C3, C4 (E), C5, C6 (E), Z2, Z1, B5, A6, A7, A8, C7

Web page: http://www.funginet.de/home.html

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B3 (E): inactive since 2012-01-01

Predictive modelling of host-fungal pathogen interactions by reconstruction of gene regulatory networks

Programme: Collaborative Research Center / Transregio 124 "Pathogenic fungi and their human host: Networks of Interaction - FungiNet"

Public web page: http://www.funginet.de/project-b3.html

Organisms: Aspergillus fumigatus, Candida albicans

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Leibniz-Institute for Natural Product Research and Infection Biology Hans Knöll Institute (HKI)

Country: Germany

City: 07745 Jena

Web page: http://www.hki-jena.de

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Showing 5 out of a possible 6 Publications Advanced Publications list for this Person with search and filtering

Survival Strategies of Pathogenic Candida Species in Human Blood Show Independent and Specific Adaptations.

INF, B3 (E), C1, C3

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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, T. Wolf, T. Conrad, S. Allert, F. Gerwien, K. Hunniger, O. Kurzai, R. Guthke, B. Hube, J. Linde, S. Brunke

Date Published: 6th Oct 2020

Publication Type: Not specified

PubMed ID: 33024045

Citation: mBio. 2020 Oct 6;11(5). pii: mBio.02435-20. doi: 10.1128/mBio.02435-20.

Created: 11th Feb 2021 at 08:45, Last updated: 17th Jan 2024 at 10:24

Human Neutrophils Produce Antifungal Extracellular Vesicles against Aspergillus fumigatus.

A1, B4, C6 (E), Z2

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Polymorphonuclear granulocytes (PMNs) are indispensable for controlling life-threatening fungal infections. In addition to various effector mechanisms, PMNs also produce extracellular vesicles (EVs). … Their contribution to antifungal defense has remained unexplored. We reveal that the clinically important human-pathogenic fungus Aspergillus fumigatus triggers PMNs to release a distinct set of antifungal EVs (afEVs). Proteome analyses indicated that afEVs are enriched in antimicrobial proteins. The cargo and the release kinetics of EVs are modulated by the fungal strain confronted. Tracking of afEVs indicated that they associated with fungal cells and even entered fungal hyphae, resulting in alterations in the morphology of the fungal cell wall and dose-dependent antifungal effects. To assess as a proof of concept whether the antimicrobial proteins found in afEVs might contribute to growth inhibition of hyphae when present in the fungal cytoplasm, two human proteins enriched in afEVs, cathepsin G and azurocidin, were heterologously expressed in fungal hyphae. This led to reduced fungal growth relative to that of a control strain producing the human retinol binding protein 7. In conclusion, extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. This finding offers an intriguing, previously overlooked mechanism of antifungal defense against A. fumigatus IMPORTANCE Invasive fungal infections caused by the mold Aspergillus fumigatus are a growing concern in the clinic due to the increasing use of immunosuppressive therapies and increasing antifungal drug resistance. These infections result in high rates of mortality, as treatment and diagnostic options remain limited. In healthy individuals, neutrophilic granulocytes are critical for elimination of A. fumigatus from the host; however, the exact extracellular mechanism of neutrophil-mediated antifungal activity remains unresolved. Here, we present a mode of antifungal defense employed by human neutrophils against A. fumigatus not previously described. We found that extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. In the end, antifungal extracellular vesicle biology provides a significant step forward in our understanding of A. fumigatus host pathogenesis and opens up novel diagnostic and therapeutic possibilities.

Authors: I. A. Shopova, I. Belyaev, P. Dasari, S. Jahreis, M. C. Stroe, Z. Cseresnyes, A. K. Zimmermann, A. Medyukhina, C. M. Svensson, T. Kruger, V. Szeifert, S. Nietzsche, T. Conrad, M. G. Blango, O. Kniemeyer, M. von Lilienfeld-Toal, P. F. Zipfel, E. Ligeti, M. T. Figge, A. A. Brakhage

Date Published: 14th Apr 2020

Publication Type: Not specified

PubMed ID: 32291301

Citation: mBio. 2020 Apr 14;11(2). pii: mBio.00596-20. doi: 10.1128/mBio.00596-20.

Created: 15th Feb 2021 at 09:34, Last updated: 17th Jan 2024 at 10:24

Module-detection approaches for the integration of multilevel omics data highlight the comprehensive response of Aspergillus fumigatus to caspofungin.

INF, A1, C5

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BACKGROUND: Omics data provide deep insights into overall biological processes of organisms. However, integration of data from different molecular levels such as transcriptomics and proteomics, still … remains challenging. Analyzing lists of differentially abundant molecules from diverse molecular levels often results in a small overlap mainly due to different regulatory mechanisms, temporal scales, and/or inherent properties of measurement methods. Module-detecting algorithms identifying sets of closely related proteins from protein-protein interaction networks (PPINs) are promising approaches for a better data integration. RESULTS: Here, we made use of transcriptome, proteome and secretome data from the human pathogenic fungus Aspergillus fumigatus challenged with the antifungal drug caspofungin. Caspofungin targets the fungal cell wall which leads to a compensatory stress response. We analyzed the omics data using two different approaches: First, we applied a simple, classical approach by comparing lists of differentially expressed genes (DEGs), differentially synthesized proteins (DSyPs) and differentially secreted proteins (DSePs); second, we used a recently published module-detecting approach, ModuleDiscoverer, to identify regulatory modules from PPINs in conjunction with the experimental data. Our results demonstrate that regulatory modules show a notably higher overlap between the different molecular levels and time points than the classical approach. The additional structural information provided by regulatory modules allows for topological analyses. As a result, we detected a significant association of omics data with distinct biological processes such as regulation of kinase activity, transport mechanisms or amino acid metabolism. We also found a previously unreported increased production of the secondary metabolite fumagillin by A. fumigatus upon exposure to caspofungin. Furthermore, a topology-based analysis of potential key factors contributing to drug-caused side effects identified the highly conserved protein polyubiquitin as a central regulator. Interestingly, polyubiquitin UbiD neither belonged to the groups of DEGs, DSyPs nor DSePs but most likely strongly influenced their levels. CONCLUSION: Module-detecting approaches support the effective integration of multilevel omics data and provide a deep insight into complex biological relationships connecting these levels. They facilitate the identification of potential key players in the organism's stress response which cannot be detected by commonly used approaches comparing lists of differentially abundant molecules.

Authors: T. Conrad, O. Kniemeyer, S. G. Henkel, T. Kruger, D. J. Mattern, V. Valiante, R. Guthke, I. D. Jacobsen, A. A. Brakhage, S. Vlaic, J. Linde

Date Published: 20th Oct 2018

Publication Type: Not specified

PubMed ID: 30342519

Citation: BMC Syst Biol. 2018 Oct 20;12(1):88. doi: 10.1186/s12918-018-0620-8.

Created: 11th Feb 2021 at 09:27, Last updated: 17th Jan 2024 at 10:24

ModuleDiscoverer: Identification of regulatory modules in protein-protein interaction networks.

INF, B1

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Abstract (Expand)

The identification of disease-associated modules based on protein-protein interaction networks (PPINs) and gene expression data has provided new insights into the mechanistic nature of diverse diseases. …

Authors: S. Vlaic, T. Conrad, C. Tokarski-Schnelle, M. Gustafsson, U. Dahmen, R. Guthke, S. Schuster

Date Published: 11th Jan 2018

Publication Type: Not specified

PubMed ID: 29323246

Citation: Sci Rep. 2018 Jan 11;8(1):433. doi: 10.1038/s41598-017-18370-2.

Created: 11th Feb 2021 at 09:20, Last updated: 17th Jan 2024 at 10:24

Data-based Reconstruction of Gene Regulatory Networks of Fungal Pathogens

FungiNet B - Bioinformatics projects, INF, B3 (E)

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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 …

Authors: , S. Gerber, , S. Vlaic, S. Durmus, T. Cakir, F. E. Sevilgen, ,

Date Published: 22nd Apr 2016

Publication Type: Not specified

PubMed ID: 27148247

Citation:

Created: 10th May 2016 at 08:25, Last updated: 17th Jan 2024 at 10:24

View all 6 Publications

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