| 1. |
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| 2. |
- Björnsdottir, Halla, et al.
(author)
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Phenol-soluble Modulin α Peptide Toxins from aggressive Staphylococcus aureus induce rapid Formation of neutrophil extracellular Traps through a reactive Oxygen species-independent Pathway
- 2017
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Journal article (peer-reviewed)abstract
- Neutrophils have the ability to capture and kill microbes extracellularly through the formation of neutrophil extracellular traps (NETs). These are DNA and protein structures that neutrophils release extracellularly and are believed to function as a defense mechanism against microbes. The classic NET formation process, triggered by, e.g., bacteria, fungi, or by direct stimulation of protein kinase C through phorbol myristate acetate, is an active process that takes several hours and relies on the production of reactive oxygen species (ROS) that are further modified by myeloperoxidase (MPO). We show here that NET-like structures can also be formed by neutrophils after interaction with phenol-soluble modulin alpha (PSM alpha) that are cytotoxic membrane-disturbing peptides, secreted from community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The PSMa-induced NETs contained the typical protein markers and were able to capture microbes. The PSMa-induced NET structures were disintegrated upon prolonged exposure to DNase-positive S. aureus but not on exposure to DNase-negative Candida albicans. Opposed to classic NETosis, PSMa-triggered NET formation occurred very rapidly, independently of ROS or MPO, and was also manifest at 4 degrees C. These data indicate that rapid NETs release may result from cytotoxic membrane disturbance by PSMa peptides, a process that may be of importance for CA-MRSA virulence.
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| 3. |
- Delgado, Camila, et al.
(author)
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Pseudomonas aeruginosa Regulated Intramembrane Proteolysis : Protease MucP Can Overcome Mutations in the AlgO Periplasmic Protease To Restore Alginate Production in Nonmucoid Revertants
- 2018
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In: Journal of Bacteriology. - : American Society for Microbiology. - 0021-9193 .- 1098-5530. ; 200:16
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Journal article (peer-reviewed)abstract
- The progression of cystic fibrosis (CF) from an acute to a chronic disease is often associated with the conversion of the opportunistic pathogen Pseudomonas aeruginosa from a nonmucoid form to a mucoid form in the lung. This conversion involves the constitutive synthesis of the exopolysaccharide alginate, whose production is under the control of the AlgT/U sigma factor. This factor is regulated posttranslationally by an extremely unstable process and has been commonly attributed to mutations in the algT (algU) gene. By exploiting this unstable phenotype, we isolated 34 spontaneous nonmucoid variants arising from the mucoid strain PDO300, a PAO1 derivative containing the mucA22 allele commonly found in mucoid CF isolates. Complementation analysis using a minimal tiling path cosmid library revealed that most of these mutants mapped to two protease-encoding genes, algO, also known as prc or PA3257, and mucP. Interestingly, our algO mutations were complemented by both mucP and algO, leading us to delete, clone, and overexpress mucP, algO, mucE, and mucD in both wild-type PAO1 and PDO300 backgrounds to better understand the regulation of this complex regulatory mechanism. Our findings suggest that the regulatory proteases follow two pathways for regulated intramembrane proteolysis (RIP), where both the AlgO/MucP pathway and MucE/AlgW pathway are required in the wild-type strain but where the AlgO/MucP pathway can bypass the MucE/AlgW pathway in mucoid strains with membrane-associated forms of MucA with shortened C termini, such as the MucA22 variant. This work gives us a better understanding of how alginate production is regulated in the clinically important mucoid variants of Pseudomonas aeruginosa. IMPORTANCE Infection by the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality seen in CF patients. Poor patient prognosis correlates with the genotypic and phenotypic change of the bacteria from a typical nonmucoid to a mucoid form in the CF lung, characterized by the overproduction of alginate. The expression of this exopolysaccharide is under the control an alternate sigma factor, AlgT/U, that is regulated posttranslationally by a series of proteases. A better understanding of this regulatory phenomenon will help in the development of therapies targeting alginate production, ultimately leading to an increase in the length and quality of life for those suffering from CF.
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| 4. |
- Ericson Jogsten, Ingrid, 1980-, et al.
(author)
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Microbial binding of perfluoroalkyl substances (PFASs)
- 2018
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In: INEF 2018. ; , s. 33-34
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Conference paper (other academic/artistic)abstract
- Per- and polyfluorinated alkyl substances (PFASs) are environmental pollutants of global concern due to their persistence and widespread occurrence in humans, wildlife and the environment. These compounds have been extensively used in various commercial and industrial applications since the mid-1900. In 2009, perfluorooctane sulfonic acid (PFOS) was added to the Stockholm convention to protect humans and wildlife from harmful effects. In Sweden, severe PFAS contamination in drinking water has resulted in elevated blood PFAS concentrations in residents living in contaminated areas.The present study evaluated microbial binding of PFASs was tested. The binding capacity was assessed in both live and dead Escherichia coli for various PFOS concentrations. The binding capacity of dead cells was higher (286-3324 μg/g of bacterial pellet) compared to live E. coli cells, showing a 5 – 7 fold lower binding capacity (38-675 μg/g of bacterial pellet). For PFOS, the affinity of branched isomers was similar to that of linear compounds. . Furthermore, other species of bacteria were tested for binding capacity of various mixtures of PFASs from both technical products and contaminated environmental waters, including Pseudomonas nitroreducens and Acidovorax delafieldii. After treatment, bacteria pellets were extracted and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Preliminary results indicate preferential binding for PFOS, the contaminant present in the highest concentration in both contaminated environmental water and spiked water of the sum of eleven PFASs recommended for analysis by the Swedish Food agency.This study gives increased knowledge of microbial binding of perfluoroalkyl substances giving insight on PFAS transport in the environment and at different trophic levels. The phenomenon of microbial binding of PFASs could also be used to establish a more cost effective remediation of PFAS contaminated waters. Further, it could lead to increased understanding of toxicological effects of PFASs related to the gut microbiota.
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| 5. |
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| 6. |
- Hosseinzadeh, Ava, et al.
(author)
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Stable Redox-Cycling Nitroxide Tempol has Antifungal and Immune-modulatory Properties
- 2019
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In: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 10
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Journal article (peer-reviewed)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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| 7. |
- Khamzeh, Arsham, et al.
(author)
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High levels of short-chain fatty acids secreted by Candida albicans hyphae induce neutrophil chemotaxis via free fatty acid receptor 2
- 2024
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In: Journal of Leukocyte Biology. - : Oxford University Press. - 1938-3673 .- 0741-5400. ; 115:3, s. 536-546
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Journal article (peer-reviewed)abstract
- Candida albicans belongs to our commensal mucosal flora and in immune-competent individuals in the absence of epithelial damage, this fungus is well tolerated and controlled by our immune defense. However, C. albicans is an opportunistic microorganism that can cause different forms of infections, ranging from superficial to life-threatening systemic infections. C. albicans is polymorphic and switches between different phenotypes (e.g. from yeast form to hyphal form). C. albicans hyphae are invasive and can grow into tissues to eventually reach circulation. During fungal infections, neutrophils in particular play a critical role for the defense, but how neutrophils are directed toward the invasive forms of fungi is less well understood. We set out to investigate possible neutrophil chemoattractants released by C. albicans into culture supernatants. We found that cell-free culture supernatants from the hyphal form of C. albicans induced both neutrophil chemotaxis and concomitant intracellular calcium transients. Size separation and hydrophobic sorting of supernatants indicated small hydrophilic factors as responsible for the activity. Further analysis showed that the culture supernatants contained high levels of short-chain fatty acids with higher levels from hyphae as compared to yeast. Short-chain fatty acids are known neutrophil chemoattractants acting via the neutrophil free fatty acid receptor 2. In line with this, the calcium signaling in neutrophils induced by hyphae culture supernatants was blocked by a free fatty acid receptor 2 antagonist and potently increased in the presence of a positive allosteric modulator. Our data imply that short-chain fatty acids may act as a recruitment signal whereby neutrophils can detect C. albicans hyphae.
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| 8. |
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| 9. |
- Lopes, José Pedro, 1986-, et al.
(author)
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Cryptococcus neoformans Induces MCP-1 Release and Delays the Death of Human Mast Cells
- 2019
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In: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 9
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Journal article (peer-reviewed)abstract
- Cryptococcosis, caused by the basidiomycete Cryptococcus neoformans, is a life-threatening disease affecting approximately one million people per year worldwide. Infection can occur when C. neoformans cells are inhaled by immunocompromised people. In order to establish infection, the yeast must bypass recognition and clearance by immune cells guarding the tissue. Using in vitro infections, we characterized the role of mast cells (MCs) in cryptococcosis. We found that MCs recognize C. neoformans and release inflammatory mediators such as tryptase and cytokines. From the latter group MCs released mainly CCL-2/MCP-1, a strong chemoattractant for monocytic cells. We demonstrated that supernatants of infected MCs recruit monocytes but not neutrophils. During infection with C. neoformans, MCs have a limited ability to kill the yeast depending on the serotype. C. neoformans, in turn, modulates the lifespan of MCs both, by presence of its polysaccharide capsule and by secreting soluble modulators. Taken together, MCs might have important contributions to fungal clearance during early stages of cryptocococis where these cells regulate recruitment of monocytes to mucosal tissues.
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| 10. |
- Lopes, Jose Pedro, 1986-, et al.
(author)
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Evasion of Immune Surveillance in Low Oxygen Environments Enhances Candida albicans Virulence
- 2018
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In: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 9:6
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Journal article (peer-reviewed)abstract
- Microbial colonizers of humans have evolved to adapt to environmental cues and to sense nutrient availability. Oxygen is a constantly changing environmental parameter in different host tissues and in different types of infection. We describe how Candida albicans, an opportunistic fungal pathogen, can modulate the host response under hypoxia and anoxia. We found that high infiltration of polymorphonuclear leukocytes (PMNs) to the site of infection contributes to a low oxygen milieu in a murine subdermal abscess. A persistent hypoxic environment did not affect viability or metabolism of PMNs. Under oxygen deprivation, however, infection with C. albicans disturbed specific PMN responses. PMNs were not able to efficiently phagocytose, produce ROS, or release extracellular DNA traps. Failure to launch an adequate response was caused by C. albicans cell wall masking of β-glucan upon exposure to low oxygen levels which hindered PAMP sensing by Dectin-1 on the surfaces of PMNs. This in turn contributed to immune evasion and enhanced fungal survival. The cell wall masking effect is prolonged by the accumulation of lactate produced by PMNs under low oxygen conditions. Finally, adaptation to oxygen deprivation increased virulence of C. albicans which we demonstrated using a Caenorhabditis elegans infection model.IMPORTANCESuccessful human colonizers have evolved mechanisms to bypass immune surveillance. Infiltration of PMNs to the site of infection led to the generation of a low oxygen niche. Exposure to low oxygen levels induced fungal cell wall masking, which in turn hindered pathogen sensing and antifungal responses by PMNs. The cell wall masking effect was prolonged by increasing lactate amounts produced by neutrophil metabolism under oxygen deprivation. In an invertebrate infection model, C. albicans was able to kill infected C. elegans nematodes within 2 days under low oxygen conditions, whereas the majority of uninfected controls and infected worms under normoxic conditions survived. These results suggest that C. albicans benefited from low oxygen niches to increase virulence. The interplay of C. albicans with innate immune cells under these conditions contributed to the overall outcome of infection. Adaption to low oxygen levels was in addition beneficial for C. albicans by reducing susceptibility to selected antifungal drugs. Hence, immunomodulation of host cells under low oxygen conditions could provide a valuable approach to improve current antifungal therapies.
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| 11. |
- Lopes, Jose Pedro, 1986-, et al.
(author)
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Opportunistic pathogen Candida albicans elicits a temporal response in primary human mast cells
- 2015
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 5
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Journal article (peer-reviewed)abstract
- Immunosuppressed patients are frequently afflicted with severe mycoses caused by opportunistic fungal pathogens. Besides being a commensal, colonizing predominantly skin and mucosal surfaces, Candida albicans is the most common human fungal pathogen. Mast cells are present in tissues prone to fungal colonization being expectedly among the first immune cells to get into contact with C. albicans. However, mast cell-fungus interaction remains a neglected area of study. Here we show that human mast cells mounted specific responses towards C. albicans. Collectively, mast cell responses included the launch of initial, intermediate and late phase components determined by the secretion of granular proteins and cytokines. Initially mast cells reduced fungal viability and occasionally internalized yeasts. C. albicans could evade ingestion by intracellular growth leading to cellular death. Furthermore, secreted factors in the supernatants of infected cells recruited neutrophils, but not monocytes. Late stages were marked by the release of cytokines that are known to be anti-inflammatory suggesting a modulation of initial responses. C. albicans-infected mast cells formed extracellular DNA traps, which ensnared but did not kill the fungus. Our results suggest that mast cells serve as tissue sentinels modulating antifungal immune responses during C. albicans infection. Consequently, these findings open new doors for understanding fungal pathogenicity.
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| 12. |
- Mangu, Jagadish, 1986-, et al.
(author)
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Per- and polyfluoroalkyl substances enhance Staphylococcus aureus pathogenicity and impair host immune response
- 2022
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In: Environmental Pollution. - : Springer. - 0269-7491 .- 1873-6424. ; 314
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Journal article (peer-reviewed)abstract
- Per- and Poly-fluoroalkyl substances (PFAS) are one of the major persistent environmental contaminants. Epidemiological studies have linked PFAS exposures to altered immunity and increased occurrence of infections in children. However, the mechanisms leading to immune susceptibility to bacterial infections remains unclear. To elucidate the mechanism, transcriptional alteration in the Caenorhabditis elegans model caused by a PFAS contaminated environmental water and two reconstituted PFAS solutions were evaluated using RNA-sequencing. PFAS affected the expression of several genes involved in C. elegans immune surveillance to Gram-positive bacteria (cpr-2, tag-38, spp-1, spp-5, clec-7, clec-172). The combined exposure to PFAS and Staphylococcus aureus significantly reduced C. elegans survival and increased intestinal membrane permeability. Furthermore, the growth of S. aureus in the presence of PFAS increased the expression of virulence genes, specifically, the virulence gene regulator saeR and α-hemolysin, hla, which resulted in increased hemolytic activity. The present study demonstrated that PFAS exposure not only increased C. elegans susceptibility to pathogens by reducing host immunity and increasing intestinal membrane permeability, but also increased bacteria virulence. This presents a broader implication for humans and other animals, where environmental contaminants simultaneously reduce host resilience, while, increasing microbial pathogenicity.
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| 13. |
- Stylianou, Konstantinos, et al.
(author)
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The goals of EU competition law : a comprehensive empirical investigation
- 2022
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In: Legal Studies. - : Cambridge University Press. - 0261-3875 .- 1748-121X. ; , s. 1-29
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Journal article (peer-reviewed)abstract
- For any field of law, the goal it was designed to achieve permeates every aspect of its application and interpretation. This is particularly true when the black letter of the law is cryptic and silent on most aspects of how it should be interpreted and applied, as is the case with competition law, which for the most part revolves around a small number of highly abstract provisions. It is only natural then that ample scholarly work has been devoted to identifying the goals and purposes of competition law. By and large these attempts have been textual, historical, and teleological. We introduce here instead a quantitative analysis of the case law and present the results of the first empirical study into the goals and purposes of EU competition law as they emerge from the entirety of the case law of the European Court of Justice, opinions of the Advocate Generals, Commission decisions, and speeches of Commissioners for Competition. This body of almost 4,000 sources paints a comprehensive picture of the underlying goals of EU competition law, and helps conclusively confirm some previous insights while debunking others, thereby helping to advance the present application and future evolution of competition law.
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| 14. |
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| 15. |
- Stylianou, Marios, et al.
(author)
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Antifungal Application of Nonantifungal Drugs
- 2014
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In: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 58:2, s. 1055-1062
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Journal article (peer-reviewed)abstract
- Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to similar to 150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis.
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| 16. |
- Stylianou, Marios, 1981-, et al.
(author)
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Distinct transcriptional response of Caenorhabditis elegans to different exposure routes of perfluorooctane sulfonic acid
- 2019
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In: Environmental Research. - : Academic Press. - 0013-9351 .- 1096-0953. ; 168, s. 406-413
-
Journal article (peer-reviewed)abstract
- Although people are exposed daily to per- and polyfluorinated alkyl substances (PFASs), the biological consequences are poorly explored. The health risks associated with PFAS exposure are currently based on chemical analysis with a weak correlation to potential harmful effects in man and animals. In this study, we show that perfluorooctane sulfonic acid (PFOS), often the most enriched PFAS in the environment, can be transferred via bacteria to higher organisms such as Caenorhabditis elegans. C. elegans nematodes were exposed to PFOS directly in buffer or by feeding on bacteria pretreated with PFOS, and this led to distinct gene expression profiles. Specifically, heavy metal and heat shock associated genes were significantly, although inversely, expressed following the different PFOS exposures. The innate immunity receptor for microbial pathogens, clec-60, was shown for the first time to be down-regulated by PFOS. This is in line with a previous study indicating that PFOS is associated with children's susceptibility to certain infectious diseases. Furthermore, bar-1, a gene associated with various cancers was highly up-regulated only when C. elegans were exposed to PFOS pretreated live bacteria. Furthermore, dead bacterial biomass had higher binding capacity for linear and isomeric PFOS than live bacteria, which correlated to the higher levels of PFOS detected in C. elegans when fed the treated E. toll, respectively. These results reveal new aspects concerning trophic chain transport of PFOS.
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| 17. |
- Stylianou, Marios, et al.
(author)
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Novel High-Throughput Screening Method for Identification of Fungal Dimorphism Blockers
- 2015
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In: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 20:2, s. 285-91
-
Journal article (peer-reviewed)abstract
- Invasive mycoses have been increasing worldwide, with Candida spp. being the most prevalent fungal pathogen causing high morbidity and mortality in immunocompromised individuals. Only few antimycotics exist, often with severe side effects. Therefore, new antifungal drugs are urgently needed. Because the identification of antifungal compounds depends on fast and reliable assays, we present a new approach based on high-throughput image analysis to define cell morphology. Candida albicans and other fungi of the Candida clade switch between different growth morphologies, from budding yeast to filamentous hyphae. Yeasts are considered proliferative, whereas hyphae are required for invasion and dissemination. Thus, morphotype switching in many Candida spp. is connected to virulence and pathogenesis. It is, consequently, reasonable to presume that morphotype blockers interfere with the virulence, thereby preventing hazardous colonization. Our method efficiently differentiates yeast from hyphal cells using a combination of automated microscopy and image analysis. We selected the parameters length/width ratio and mean object shape to quantitatively discriminate yeasts and hyphae. Notably, Z' factor calculations for these parameters confirmed the suitability of our method for high-throughput screening. As a second stage, we determined cell viability to discriminate morphotype-switching inhibitors from those that are fungicidal. Thus, our method serves as a basis for the identification of candidates for next-generation antimycotics.
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| 18. |
- Stylianou, Marios, 1981-
(author)
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Pharmaceutical And Immunollogical Challenge Of Fungal Pathogens
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Incidences of fungal infections are on the rise in immunosuppressed people. Predominant causative agents for these mycoses are species of the genus Candida, including Candida albicans, Candida glabrata and Candida dublieniensis. Despite a wide range of emerging pathogens, C. albicans remains the leading cause. According to recent epidemiological studies, blood stream infections with C. albicans cause annually ~55% mortality in approximately 300,000 patients from intensive care units worldwide. Furthermore, the percentage of morbidity linked to oral, esophageal and vulvovaginal mycoses cause by C. albicans reach up to 90%. Reasons for these medical concerns are the lack of efficient diagnostics and antifungal therapy.Here, we therefore sought to find novel antifungal strategies inspired by innate immune cells, such as neutrophils. These phagocytes are able to block the fungal pathogenicity. Neutrophils are bloodstream leukocytes serving as the first line of defense against pathogenic microbes. It has been shown that neutrophils have a strong antifungal activity by impairing the conversion of the dimorphic C. albicans from yeast to hyphal form (Y-H). Consequently, we raised the question whether other immune cells, such as mast cells, with less phagocytic cabapilities may have similar activity to neutrophils.Mast cells are tissue-dwelling cells. Mucosal tissue is rich in mast cells and usually constitutes the entry ports for fungal pathogens into the human body. A contribution of mast cells in antifungal defense is, thus, very likely. We human explored mast cell functions upon encounter with fungal pathogens. Interestingly, human mast cells show a transient potential to impair fungal viability. To understand the mechanism behind this impairment we analyzed the human mast cell functions in more detail. We found that human mast cells challenged with C. albicans, immediately degranulate and secrete distinct cytokines and chemokines in an orchestrated manner. The chemokines secreted attract neutrophils. Mast cells moreover are able to internalize fungal cells and to ‘commit suicide’ by releasing extracellular DNA traps that ensnare the pathogen. The effectiveness of future antifungals is depended on targeting the pathogen virulence with more efficiency.The dimorphism of C. albicans is proven to be essential its virulence. Blockage of this switching ability could render the pathogen avirulent. Consequently, we screened for compounds that mimic the neutrophils anti-dimorphic activity by screening small chemical molecule libraries that block Y-H transition. The screening of big chemical libraries requires a reliable, reproducible and rapid high-throughput screening assay (HTS). We developed an HTS assay based on automated microscopy and image analysis, thereby allowing to distinguish between yeast and filamentous forms. In order to find the ideal Y-H blocker, we also evaluated the cell viability via the count of ATP levels when challenged with the respective small chemical molecules. Drug development is an elaborate and expensive process. We therefore applied our screening setup to identify antidimorphic/antifungal activity in compounds from two different chemical libraries including FDA-approved drugs. The study disclosed 7 off-patent antifungal drugs that have potent antimycotic activity, including 4 neoplastic agents, 2 antipsychotic drugs and 1 antianemic medication.In a nutshell, we aimed to mimic the anti-dimorphic/antifungal activity of neutrophils with small chemical molecules. Furthermore, we elucidated how immune cells contribute to antifungal defense to exploit these mechanisms for the development of novel antifungal therapies. Thus, this thesis provides novel tools for the discovery of more efficient compounds, identifies previously unknown antifungal aspect of off-patent FDA-approved drugs and highlights the interplay of mast cells with pathogenic fungi with the aim to define new screening strategies.
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| 19. |
- Thunström Salzer, Anna, et al.
(author)
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Assessment of Neutrophil Chemotaxis Upon G-CSF Treatment of Healthy Stem Cell Donors and in Allogeneic Transplant Recipients
- 2018
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 9
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Journal article (peer-reviewed)abstract
- Neutrophils are crucial for the human innate immunity and constitute the majority of leukocytes in circulation. Thus, blood neutrophil counts serve as a measure for the immune system's functionality. Hematological patients often have low neutrophil counts due to disease or chemotherapy. To increase neutrophil counts and thereby preventing infections in high-risk patients, recombinant G-CSF is widely used as adjunct therapy to stimulate the maturation of neutrophils. In addition, G-CSF is utilized to recruit stem cells (SCs) into the peripheral blood of SC donors. Still, the actual functionality of neutrophils resulting from G-CSF treatment remains insufficiently understood. We tested the ex vivo functionality of neutrophils isolated from blood of G-CSF-treated healthy SC donors. We quantified chemotaxis, oxidative burst, and phagocytosis before and after treatment and detected significantly reduced chemotactic activity upon G-CSF treatment. Similarly, in vitro treatment of previously untreated neutrophils with G-CSF led to reduced chemotactic activity. In addition, we revealed that this effect persists in the allogeneic SC recipients up to 4 weeks after neutrophil engraftment. Our data indicates that neutrophil quantity, as a sole measure of immunocompetence in high-risk patients should be considered cautiously as neutrophil functionality might be affected by the primary treatment.
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| 20. |
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