Pathogen Oriented SNARE Trafficking for Immune Tailoring
|Title||Pathogen Oriented SNARE Trafficking for Immune Tailoring|
|Sponsor||European Research Council - Consolidator Grant (ERC-CoG)|
|Institution||University of Groningen|
|Principal investigator||Geert van den Bogaart
Associated cell lines
Immune 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 the 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 lead to better vaccinations and therapies for infectious diseases.