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Research project (§ 26 & § 27)
Duration : 2021-09-01 - 2024-08-31

The parasite fluke Opisthorchis felinus belongs to the Opisthorchiidae family which also includes Opisthorchis viverrini and Clonorchis sinensis. Millions of people in Asia and Eastern Europe, where these flukes are endemic, are already infected or at risk. The parasites success in infection is often linked with surface oligosaccharides presented to the host. This protein linked glyconjugates also called N- and O-linked glycans play a role either in binding and parasitic infection, or on the immune-host response they trigger in humans. Unfortunately, to date very little is known about the glycoconjugate structures of liver flukes and especially O. felinus glycans. Considering the disease severity caused by the parasite, which can even induce cancers such as cholangiocarcinoma, there is a great need to expand the knowledge on the glycoconjugates structures and their interaction with the immune system. In this project we aim to combine modern and powerful analytical tools such as metabolomics, glycomics, transcriptomics, microbiome, and glycoproteome analysis with coupled online and offline liquid chromatography- mass spectrometry approaches on proteins from (i) adult worms, eggs and excretory products and from (ii) bile juice and faeces from infected patients. The purified glycans will be subject to detailed epitope identification and in vitro cell based assays for a better understanding of the host immune response after parasite infection.
Research project (§ 26 & § 27)
Duration : 2020-11-02 - 2023-11-01

Human heme peroxidases figure prominently in human biology by contributing to tissue development and architecture, thyroid hormone biosynthesis and innate immunity. Myeloperoxidase (MPO), eosinophil peroxidase (EPO) and lactoperoxidase (LPO) exhibit an indispensable role in microbial killing by releasing potent antimicrobial oxidants. However, these reaction products may also adversely affect tissues and cause acute and chronic inflammatory diseases. Consequently, there is a need for highly selective inhibitors for MPO, EPO and LPO with no risk of off-target effects, i.e. interference with thyroid peroxidase and peroxidasin 1, which share a similar heme cavity architecture. It has been found that pathogenic bacteria like Staphylococcus aureus have evolved a broad repertoire of strategies to resist microbial killing including SPIN (Staphylococcal Peroxidase INhibitor) that binds tightly to MPO and inhibits its enzymatic activity. SPIN shares no sequence homology to other known proteins and consists of two functionally distinct domains, i.e. a small N-terminal domain which acts as a molecular plug of the access channel and a C-terminal domain which mediates the specific binding to human MPO. This project will characterize the structural basis as well as the thermodynamics and kinetics of binding of SPIN-aureus to and inhibition of MPO including its interference with the individual reaction steps in the halogenation and peroxidase cycle of MPO. We further aim to understand the structure and function of recently identified SPIN-aureus homologs from other staphylococcal species and of an artificially designed SPIN-consensus protein that binds to both MPO and EPO. These investigations will include both comprehensive biochemical and biophysical investigations as well as molecular dynamics simulations. These studies will provide the basis for the design of specific binders and inhibitors for human peroxidases. In detail, we aim to design specific inhibitors for MPO, EPO and LPO employing (i) a rational design including saturation mutagenesis and chemical engineering of the N-terminal plug and (ii) directed evolution of the binding domain for specific interaction with MPO, EPO and LPO using yeast surface display combined with fluorescence activated cell sorting of newly generated SPIN libraries. Summing up, this project will provide (i) the fundamental biochemical understanding of the interaction of SPIN proteins with the human heme peroxidases as well as (ii) will design and select SPIN-based inhibitors of MPO, EPO and LPO. Future studies will focus on the application and further development of these lead candidates as potential drugs in in vitro and in vivo studies.
Research project (§ 26 & § 27)
Duration : 2021-01-01 - 2024-12-31

Wider research context / theoretical framework: Glycans cover the surfaces of all cells and are vary between species and phyla. Hypotheses/research questions /objectives: Based on previous work by us and others, the major underlying hypotheses are that: (i) anionic/zwitterionic modifications of N-glycans vary between orders and species of arthropods and these structures are either (ii) bound by mammalian immune lectins involved, e.g., in recognition of arthropod-derived viruses, (iii) involved in interactions of pathogens with arthropods (e.g., mosquitoes) as intermediate or final hosts or (iv) have innate function, e.g., in development of the arthropod species itself. Approach/methods Enzymatic remodelling of saccharides, preparation/analysis of natural glycans from selected insects and probing saccharides/glycans in an microarray format with lectins, pentraxins and antibodies. Level of originality / innovation The project has the goal of delivering new information about insect glycomes.

Supervised Theses and Dissertations