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  • American Society for Microbiology  (3)
  • 2015-2019  (3)
  • 1
    Online Resource
    Online Resource
    Rubella Viruses Shift Cellular Bioenergetics to a More Oxidative and Glycolytic Phenotype with a Strain-Specific Requirement for Glutamine
    American Society for Microbiology ; 2018
    In:  Journal of Virology Vol. 92, No. 17 ( 2018-09)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 92, No. 17 ( 2018-09)
    Abstract: The flexible regulation of cellular metabolic pathways enables cellular adaptation to changes in energy demand under conditions of stress such as posed by a virus infection. To analyze such an impact on cellular metabolism, rubella virus (RV) was used in this study. RV replication under selected substrate supplementation with glucose, pyruvate, and glutamine as essential nutrients for mammalian cells revealed its requirement for glutamine. The assessment of the mitochondrial respiratory (based on the oxygen consumption rate) and glycolytic (based on the extracellular acidification rate) rate and capacity by respective stress tests through Seahorse technology enabled determination of the bioenergetic phenotype of RV-infected cells. Irrespective of the cellular metabolic background, RV infection induced a shift of the bioenergetic state of epithelial cells (Vero and A549) and human umbilical vein endothelial cells to a higher oxidative and glycolytic level. Interestingly there was a RV strain-specific, but genotype-independent demand for glutamine to induce a significant increase in metabolic activity. While glutaminolysis appeared to be rather negligible for RV replication, glutamine could serve as donor of its amide nitrogen in biosynthesis pathways for important metabolites. This study suggests that the capacity of RVs to induce metabolic alterations could evolve differently during natural infection. Thus, changes in cellular bioenergetics represent an important component of virus-host interactions and could complement our understanding of the viral preference for a distinct host cell population. IMPORTANCE RV pathologies, especially during embryonal development, could be connected with its impact on mitochondrial metabolism. With bioenergetic phenotyping we pursued a rather novel approach in virology. For the first time it was shown that a virus infection could shift the bioenergetics of its infected host cell to a higher energetic state. Notably, the capacity to induce such alterations varied among different RV isolates. Thus, our data add viral adaptation of cellular metabolic activity to its specific needs as a novel aspect to virus-host evolution. In addition, this study emphasizes the implementation of different viral strains in the study of virus-host interactions and the use of bioenergetic phenotyping of infected cells as a biomarker for virus-induced pathological alterations.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.00934-18
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
    detail.hit.zdb_id: 1495529-5
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Quinolone Amides as Antitrypanosomal Lead Compounds with In Vivo Activity
    American Society for Microbiology ; 2016
    In:  Antimicrobial Agents and Chemotherapy Vol. 60, No. 8 ( 2016-08), p. 4442-4452
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 60, No. 8 ( 2016-08), p. 4442-4452
    Abstract: Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against Trypanosoma brucei brucei . Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding ( 〉 99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with T. b. rhodesiense (STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01757-15
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2016
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 3
    Online Resource
    Online Resource
    Serum Amyloid P Component Binds Fungal Surface Amyloid and Decreases Human Macrophage Phagocytosis and Secretion of Inflammatory Cytokines
    American Society for Microbiology ; 2019
    In:  mBio Vol. 10, No. 2 ( 2019-04-30)
    Details
    In: mBio, American Society for Microbiology, Vol. 10, No. 2 ( 2019-04-30)
    Abstract: In patients with invasive fungal diseases, there is often little cellular inflammatory response. We tested the idea that binding of the human constitutive plasma protein serum amyloid P component (SAP) (also called PTX2) to Candida albicans dampens the innate immune response to this fungus. Many pathogenic fungi have cell surface amyloid-like structures important for adhesion and biofilm formation. Human SAP bound to fungi that expressed functional cell surface amyloid, but SAP had minimal binding to fungi with reduced expression of cell surface amyloid. In the absence of SAP, phagocytosis of fungi by human macrophages was potentiated by expression of amyloid on the fungi. SAP binding to fungi inhibited their phagocytosis by macrophages. Macrophages pretreated with SAP displayed reduced fungal phagocytosis, reduced secretion of inflammatory cytokines (IFN-γ, IL-6, and TNF-α), and increased secretion of the anti-inflammatory cytokine IL-10. SAP bound to fungi or added to the medium upregulated the expression of the anti-inflammatory receptor CD206 on macrophages. These findings suggest that SAP bound to amyloid-like structures on fungal cells dampens the host cellular immune response in fungal diseases such as invasive candidiasis. IMPORTANCE Macrophages are a key part of our innate immune system and are responsible for recognizing invading microbes, ingesting them, and sending appropriate signals to other immune cells. We have found that human macrophages can recognize invading yeast pathogens that have a specific molecular pattern of proteins on their surfaces: these proteins have structures similar to the structures of amyloid aggregates in neurodegenerative diseases like Alzheimer’s disease. However, this surface pattern also causes the fungi to bind a serum protein called serum amyloid P component (SAP). In turn, the SAP-coated yeasts are poorly recognized and seldom ingested by the macrophages, and the macrophages have a more tolerant and less inflammatory response in the presence of SAP. Therefore, we find that surface structures on the yeast can alter how the macrophages react to invading microbes.
    Type of Medium: Online Resource
    ISSN: 2161-2129 , 2150-7511
    URL: Article
    DOI: 10.1128/mBio.00218-19
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
    detail.hit.zdb_id: 2557172-2
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