| 1. |
- Hosseinzadeh, Ava, et al.
(författare)
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Stable Redox-Cycling Nitroxide Tempol has Antifungal and Immune-modulatory Properties
- 2019
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Invasive mycoses remain underdiagnosed and difficult to treat. Hospitalized individuals with compromised immunity increase in number and constitute the main risk group for severe fungal infections. Current antifungal therapy is hampered by slow and insensitive diagnostics and frequent toxic side effects of standard antifungal drugs. Identification of new antifungal compounds with high efficacy and low toxicity is therefore urgently required. We investigated the antifungal activity of tempol, a cell-permeable nitroxide. To narrow down possible mode of action we used RNA-seq technology and metabolomics to probe for pathways specifically disrupted in the human fungal pathogen Candida albicans due to tempol administration. We found genes upregulated which are involved in iron homeostasis, mitochondrial stress, steroid synthesis, and amino acid metabolism. In an ex vivo whole blood infection, tempol treatment reduced C. albicans colony forming units and at the same time increased the release of pro-inflammatory cytokines, such as interleukin 8 (IL-8, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor). In a systemic mouse model, tempol was partially protective with a significant reduction of fungal burden in the kidneys of infected animals during infection onset. The results obtained propose tempol as a promising new antifungal compound and open new opportunities for the future development of novel therapies.
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| 2. |
- Niemiec, Maria Joanna, 1984-, et al.
(författare)
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Dual transcriptome of the immediate neutrophil and Candida albicans interplay
- 2017
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neutrophils are traditionally considered transcriptionally inactive. Compared to other immune cells, little is known about their transcriptional profile during interaction with pathogens. Methods: We analyzed the meta-transcriptome of the neutrophil-Candida albicans interplay and the transcriptome of C. albicans challenged with neutrophil extracellular traps (NETs) by RNA-Seq, considering yeast and hypha individually in each approach. Results: The neutrophil response to C. albicans yeast and hyphae was dominated by a morphotype-independent core response. However, 11 % of all differentially expressed genes were regulated in a specific manner when neutrophils encountered the hyphal form of C. albicans. While involving genes for transcriptional regulators, receptors, and cytokines, the neutrophil core response lacked typical antimicrobial effectors genes. Genes of the NOD-like receptor pathway, including NLRP3, were enriched. Neutrophil-and NET-provoked responses in C. albicans differed. At the same time, the Candida transcriptome upon neutrophil encounter and upon NET challenge included genes from various metabolic processes and indicate a mutual role of the regulators Tup1p, Efg1p, Hap43p, and Cap1p. Upon challenge with neutrophils and NETs, the overall Candida response was partially morphotype-specific. Yet again, actual oppositional regulation in yeasts and hyphae was only detected for the arginine metabolism in neutrophil-infecting C. albicans. Conclusions: Taken together, our study provides a comprehensive and quantitative transcript profile of the neutrophil-C. albicans interaction. By considering the two major appearances of both, neutrophils and C. albicans, our study reveals yet undescribed insights into this medically relevant encounter. Hence, our findings will facilitate future research and potentially inspire novel therapy developments.
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| 3. |
- Sohn, Kai, et al.
(författare)
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Getting in touch with Candida albicans : the cell wall of a fungal pathogen
- 2006
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Ingår i: Current Drug Targets. - : Bentham Science Publishers Ltd.. - 1389-4501 .- 1873-5592. ; 7:4, s. 505-512
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Tidskriftsartikel (refereegranskat)abstract
- The cell wall of fungi is a highly complex structure consisting of a network of polysaccharides in which a plethora of different proteins are embedded. It is one of the major organelles of the cell surrounding it like an armor which protects from environmental stresses like osmotic pressure and defines the shape and physical strength of the fungal cell. It is crucial for colonization and infection since it defines the interface between host and pathogen. No similar structure is present in the host, therefore it defines a prime target for drug development. In this context, it has been shown that cell surface proteins are required for adhesion to host cells. The fact, that both pathogenic fungi, like Candida albicans as well as non-pathogenic fungi, like Saccharomyces cerevisiae, in general, have a very similar polysaccharide structure but differ significantly in their protein composition which underscores the importance of cell wall proteins for pathogenesis. However, cell wall proteomics of fungi is a highly challenging task due to the complex biochemistry of these proteins. The extensive post-translational modifications and covalent attachment to the polysaccharide backbone of a large proportion of cell wall proteins makes it a demanding task to isolate and identify them. In this article, we describe the recent approaches that have been developed to describe cell wall dynamics and to isolate and identify cell wall proteins in the pathogenic yeast C. albicans.
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| 4. |
- Urban, Constantin, et al.
(författare)
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The moonlighting protein Tsa1p is implicated in oxidative stress response and in cell wall biogenesis in Candida albicans
- 2005
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Ingår i: Molecular Microbiology. - : Wiley-Blackwell. - 0950-382X .- 1365-2958. ; 57:5, s. 1318-1341
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Tidskriftsartikel (refereegranskat)abstract
- Candida albicans is one of the most common fungal pathogens in humans. The cell wall is the first contact site between host and pathogen and thus is critical for colonization and infection of the host. We have identified Tsa1p, a protein that is differentially localized to the cell wall of C. albicans in hyphal cells but remains in the cytosol and nucleus in yeast-form cells. This is different from Saccharomyces cerevisiae, where the homologous protein solely has been found in the cytoplasm. We report here that TSA1 confers resistance towards oxidative stress as well as is involved in the correct composition of hyphal cell walls. However, no significant change of the cell wall composition was observed in a TSA1 deletion strain in yeast-form cells, which is in good agreement with the observation that Tsa1p is absent from the yeast-form cell wall. This indicates that Tsa1p of C. albicans might represent a moonlighting protein with specific functions correlating to its respective localization. Furthermore, the translocation of Tsa1p to the hyphal cell wall of C. albicans depends on Efg1p, suggesting a contribution of the cAMP/PKA pathway to the localization of this protein. In a strain deleted for TUP1 that filaments constitutively Tsa1p can be found in the cell wall under all conditions tested, confirming the result that Tsa1p localization to the cell wall is correlated to the morphology of C. albicans.
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