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Dynamics of DC-SIGN microdomains mediating recognition and uptake of viruses by dendritic cells


Dendritic cells (DCs) are the sentinels of the immune system. They are bone marrow-derived, phagocytic cells, located in tissues to patrol for foreign antigens and present them to T cells. DC-SIGN is a DC-specific C-type lectin involved in adhesion and in pathogen-recognition, interacting with carbohydrate structures in a Ca2+-dependent manner. Life-threatening viruses like HIV-1, Ebola, and Hepatitis C virus are recognized by DC-SIGN. By high-resolution electron microscopy (EM), the applicant showed that o n DC cell membrane DC-SIGN can exist in two forms: randomly distributed or in submicron-sized (200 nm diameter) microdomains.
These microdomains were shown to reside in lipid rafts and to be required for efficient binding and uptake of virus. How DC-SIGN m icrodomains are formed is largely unknown. The aim of this proposal is to follow the dynamics of DC-SIGN microdomains in living cells with high spatial and temporal resolution.
Two aspects will be investigated: formation and stability of DC-SIGN microdomai ns as well as microdomain-mediated internalization and routing of virus-like particles. Fluorescence Resonance Energy Transfer (FRET) is a powerful tool for imaging molecular activities of suitably labeled DC-SIGN molecules in living cells. Ligand-coated h ighly-photostable Quantum Dots are excellent fluorescent probes for monitoring endocytosis and vesicular trafficking mediated by DC-SIGN micro-domains. Currently, DCs are manipulated ex vivo for the development of anti-tumour and anti-virus therapies.
Therefore, this project will provide relevant information for important health-care areas, such as
i) development of C-type lectin-based vaccines against invading pathogens;
ii) study of antigen-routing mechanisms in DC cross-presentation; and iii) development o f C-type lectin-based targeting of DCs in anti-tumour strategies.

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