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1. Peters, Simon. The impact of sphingolipids on \(Neisseria\) \(meningitidis\) and their role in meningococcal pathogenicity.
Degree: PhD, Graduate Schools, 2021, Universität Würzburg
The obligate human pathogen Neisseria meningitidis is a major cause of sepsis and meningitis worldwide. It affects mainly toddlers and infants and is responsible for thousands of deaths each year. In this study, different aspects of the importance of sphingolipids in meningococcal pathogenicity were investigated. In a first step, the acid sphingomyelinase (ASM), which degrades membrane sphingomyelin to ceramide, was studied in the context of meningococcal infection. A requirement for ASM surface activity is its translocation from the lysosomal compartment to the cell surface, a process that is currently poorly understood. This study used various approaches, including classical invasion and adherence assays, flow cytometry, and classical and super resolution immunofluorescence microscopy (dSTORM). The results showed that the live, highly piliated N. meningitidis strain 8013/12 induced calcium-dependent ASM translocation in human brain microvascular endothelial cells (HBMEC). Furthermore, it promoted the formation of ceramide-rich platforms (CRPs). In addition, ASM translocation and CRP formation were observed after treating the cells with pili-enriched fractions derived from the same strain. The importance for N. meningitidis to utilize this pathway was shown by the inhibition of the calcium-dependent ASM translocation, which greatly decreased the number of invasive bacteria. I also investigated the importance of the glycosphingolipids GM1 and Gb3. The results showed that GM1, but not Gb3, plays an important role in the ability of N. meningitidis to invade HBMEC. By combining dSTORM imaging and microbiological approaches, we demonstrated that GM1 accumulated prolifically around bacteria during the infection, and that this interaction seemed essential for meningococcal invasion. Sphingolipids are not only known for their beneficial effect on pathogens. Sphingoid bases, including sphingosine, are known for their antimicrobial activity. In the last part of this study, a novel correlative light and electron microscopy approach was established in the combination with click chemistry to precisely localize azido-functionalized sphingolipids in N. meningitidis. The result showed a distinct concentration-dependent localization in either the outer membrane (low concentration) or accumulated in the cytosol (high concentration). This pattern was confirmed by mass spectrometry on separated membrane fractions. Our data provide a first insight into the underlying mechanism of antimicrobial sphingolipids.
Der obligate Humanpathogen Neisseria meningitidis ist weltweit einer der Hauptursachen für Sepsis und Meningitis. Er befällt vor allem Kleinkinder und Säuglinge und ist jedes Jahr für Tausende von Todesfällen verantwortlich. In dieser Studie wurden verschiedene Aspekte der Bedeutung von Sphingolipiden bei der Pathogenität von Meningokokken untersucht. In einem ersten Schritt wurde die saure Sphingomyelinase (ASM), die Membran-Sphingomyelin zu Ceramid abbaut, im Zusammenhang mit einer Meningokokken-Infektion untersucht. Eine…Advisors/Committee Members: Schubert-Unkmeir, A. (referee), Sauer, M. (referee), Johswich, Kay (referee).
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APA (6th Edition):
Peters, S. (2021). The impact of sphingolipids on \(Neisseria\) \(meningitidis\) and their role in meningococcal pathogenicity. (Doctoral Dissertation). Universität Würzburg. Retrieved from https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/22623; 10.25972/OPUS-22623
Chicago Manual of Style (16th Edition):
Peters, Simon. “The impact of sphingolipids on \(Neisseria\) \(meningitidis\) and their role in meningococcal pathogenicity.” 2021. Doctoral Dissertation, Universität Würzburg. Accessed April 22, 2021. https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/22623; 10.25972/OPUS-22623.
MLA Handbook (7th Edition):
Peters, Simon. “The impact of sphingolipids on \(Neisseria\) \(meningitidis\) and their role in meningococcal pathogenicity.” 2021. Web. 22 Apr 2021.
Peters S. The impact of sphingolipids on \(Neisseria\) \(meningitidis\) and their role in meningococcal pathogenicity. [Internet] [Doctoral dissertation]. Universität Würzburg; 2021. [cited 2021 Apr 22]. Available from: https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/22623; 10.25972/OPUS-22623.
Council of Science Editors:
Peters S. The impact of sphingolipids on \(Neisseria\) \(meningitidis\) and their role in meningococcal pathogenicity. [Doctoral Dissertation]. Universität Würzburg; 2021. Available from: https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/22623; 10.25972/OPUS-22623