ORCID Profile
0000-0002-9379-9792
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Publisher: Cold Spring Harbor Laboratory
Date: 10-05-2021
DOI: 10.1101/2021.05.10.443458
Abstract: Glycan-binding proteins, so-called lectins, are exposed on mammalian cell surfaces and decipher the information encoded within glycans translating it into biochemical signal transduction pathways in the cell. These glycan-lectin communication pathways are complex and difficult to analyse. However, quantitative data with single cell resolution provides means to disentangle the associated signalling cascades. We chose C-Type lectin receptors (CLRs) expressed on immune cells as a model system to study their capacity to transmit information encoded in glycans of incoming particles. Lectin receptor NFκB-reporter cell lines expressing DC-SIGN, MCL, dectin-1, dectin-2, and mincle, as well as TNFαR and TLR-1& in monocytic cell lines were characterized by comparing their efficiency to transmit glycan-encoded information. The information content was measured by following NFκB dependent GFP expression. While most receptors did transmit information to NFκB efficiently, we found dectin-2 to be an inefficient signalling receptor. Yet upon closer analysis we show that the sensitivity of the dectin-2 signal transduction pathway (EC 50 ) can be enhanced by overexpression of its co-receptor FcRγ, while its transmitted information cannot. In this context, we expanded our investigation towards the integration of multiple signal transduction pathways, which is crucial during pathogen recognition. We show how lectin receptors using a similar signal transduction pathway (dectin-1 and dectin-2) are being integrated by striking a compromise between the lectins. By using dectin-2 and other lectins as ex le we demonstrate how cellular heterogeneity and the receptor itself determine the efficiency and therefore outcome of the signal transduction pathways.
Publisher: S. Karger AG
Date: 29-05-2019
DOI: 10.1159/000500547
Abstract: Langerhans cells are key sentinel cells of the skin and mucosal lining. They sense microorganisms through their repertoire of pattern-recognition receptors to mount and direct appropriate immune responses. We recently demonstrated that human Langerhans cells interact with the Gram-positive pathogen i Staphylococcus aureus /i through the Langerhans cell-specific receptor langerin (CD207). It was previously hypothesized that two linked single nucleotide polymorphisms (SNPs N288D and K313I) in the carbohydrate recognition domain of langerin would affect interaction with microorganisms. We show that recognition of i S. aureus /i by recombinant langerin molecules is abrogated in the co-inheriting SNP variant, which is mainly explained by the N288D SNP and further enhanced by K313I. Moreover, introduction of SNP N288D in ectopically-expressed langerin affected cellular distribution of the receptor such that langerin displayed enhanced plasma membrane i /i expression. Despite this increased binding of i S. aureus /i by the langerin double SNP variant, uptake of bacteria by this langerin variant was compromised. Our findings indicate that in a proportion of the human population, the recognition and uptake of i S. aureus /i by Langerhans cells may be affected, which could have important consequences for proper immune activation and i S. aureus /i -associated disease.
Publisher: American Chemical Society (ACS)
Date: 27-11-2018
DOI: 10.1021/ACSCHEMBIO.8B00875
Abstract: Fragment-based drug discovery is a powerful complement to conventional high-throughput screening, especially for difficult targets. Screening low-molecular-weight fragments usually requires highly sensitive biophysical methods, because of the generally low affinity of the identified ligands. Here, we developed a cell-based fragment screening assay (cellFy) that allows sensitive identification of fragment hits in a physiologically more relevant environment, in contrast to isolated target screenings in solution. For this, a fluorescently labeled multivalent reporter was employed, enabling direct measurement of displacement by low-molecular-weight fragments without requiring enzymatic reactions or receptor activation. We applied this technique to identify hits against two challenging targets of the C-type lectin receptor (CLR) family: Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN) and Langerin. Both receptors are involved in pathogen recognition and initiation of an immune response, which renders them attractive targets for immune modulation. Because of their shallow and hydrophilic primary binding site, hit identification for CLRs is challenging and druglike ligands for CLRs are sparse. Screening of a fragment library followed by hit validation identified several promising candidates for further fragment evolution for DC-SIGN. In addition, a multiplexed assay format was developed for simultaneous screening against multiple CLRs, allowing a selectivity counterscreening. Overall, this sensitive cell-based fragment screening assay provides a powerful tool for rapid identification of bioactive fragments, even for difficult targets.
Publisher: American Chemical Society (ACS)
Date: 10-05-2019
Publisher: Wiley
Date: 11-06-2020
Publisher: American Society for Microbiology
Date: 25-06-2019
Abstract: The bacterium Staphylococcus aureus is an important cause of skin infections and is also associated with the occurrence and severity of eczema. Langerhans cells (LCs), a specific subset of skin immune cells, participate in the immune response to S. aureus , but it is yet unclear how LCs recognize S. aureus . Therefore, we investigated the molecular mechanism underlying the interaction between LCs and S. aureus . We identified that wall teichoic acid, an abundant polymer on the S. aureus surface, is recognized by langerin, a receptor unique to LCs. This interaction allows LCs to discriminate S. aureus from other related staphylococcal species and initiates a proinflammatory response similar to that observed in patients with eczema. Our data therefore provide important new insights into the relationship between S. aureus , LCs, and eczema.
No related grants have been discovered for Felix F. Fuchsberger.