Project description
Mechanisms of selective pathogen presentation in immune response
Immune clearance of infection requires T-cell activation by macrophages and dendritic cells presenting peptides derived from ingested pathogens on major histocompatibility complexes. Presentation of the minority of ingested pathogens is promoted by phagosome-autonomous trafficking where the pathogen binding to Toll-like receptors in phagosomes triggers recruitment of proteases and transporters to them but not other phagosomes present in the cell, promoting specific presentation of pathogen-derived peptides. The goal of the EU-funded project POST-IT is to determine mechanisms of selectivity for presentation of pathogen-derived over harmless self-antigens. Project work will be based on the hypothesis that Toll-like receptor signalling triggers phosphorylation of SNARE proteins that are molecular motors driving the fusion of the phagosomal membrane. This study will explain the high specificity of the adaptive immune system for pathogens and could lead to better therapies for infectious diseases in the future.
Objective
ImImmune clearance of infectious diseases requires correct T cell activation by macrophages and dendritic cells (DCs) that present peptides derived from ingested pathogens on major histocompatibility complexes (MHC). Yet, macrophages and DCs also ingest self-antigens present in healthy cells and their presentation might trigger autoimmune disease. Presentation of the minority of ingested pathogens is promoted by so-called phagosome-autonomous trafficking. Here, pathogen binding to Toll-like receptors in phagosomes triggers recruitment of proteases and transporters to these phagosomes, but not to other phagosomes present in the same cell, promoting specific presentation of pathogen-derived peptides. However, a molecular understanding of this pathogen-oriented phagosome-autonomous trafficking is lacking.
The goal of this project is to determine how phagosome-autonomous pathogen recognition promotes presentation of pathogen-derived over harmless self-antigens. Based on my preliminary data and literature, I hypothesize that Toll-like receptor signaling triggers phosphorylation of multiple SNARE proteins at the phagosomal membrane. As SNARE phosphorylation can promote or prevent membrane fusion, this alters delivery of proteases and transporters to these phagosomes, which in turn promotes presentation of pathogen-derived peptides.
Objective 1 is to determine how SNARE function is altered upon pathogen-recognition in phagosomes using my novel quantitative Förster resonance energy transfer-fluorescence lifetime imaging microscopy (FRET-FLIM)-based technique. Objective 2 is to address how Toll-like receptor-mediated SNARE phosphorylation affects phagosome-autonomous trafficking. Objective 3 is to resolve the functional roles of SNAREs in antigen presentation using a novel bio-orthogonal chemistry-based method. This study will explain the high sensitivity of the adaptive immune system for pathogens and could lead to better vaccinations and therapies for infectious diseases.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsmicroscopy
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Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
9712CP Groningen
Netherlands