Spatial and temporal control of self/non-self discrimination in innate immunity: TLRstorm

Programme(s): H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
Topic(s): MSCA-IF-2018 - Individual Fellowships
Call for proposal: H2020-MSCA-IF-2018
Funding Scheme: MSCA-IF-EF-RI - RI – Reintegration panel

Grant agreement ID: 841440

Project description
Molecular control of self-tolerance to nucleic acids in innate immunity
The recognition of nucleic acids allows the detection of diverse pathogens by a limited number of innate immune receptors but increases the threat of a potential autoimmune response. Toll-like receptors (TLR) TLR7 and TLR9 can recognise self RNA or DNA and contribute to autoimmune diseases. It is therefore important to define their subcellular localisation and learn how they are coordinated in time to fully understand TLR regulation and avoid self-recognition. The EU-funded TLRstorm project aims to investigate fundamental aspects of TLR biology. State-of-the-art sub-diffraction imaging techniques will provide insight into the spatial and temporal control of TLR signalling and help us define the molecular principles that maintain self-tolerance to nucleic acids.

Objective
Recognition of nucleic acids enables detection of diverse pathogens by a limited number of innate immune receptors, but also exposes the host to potential autoimmunity. At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self-RNA or DNA, respectively, and contribute to the pathology of autoimmune diseases. Despite the structural and functional similarities between these two receptors, they can have opposing effects in autoimmune diseases such as systemic lupus erythematosus. The fellow's previous studies have identified a potential explanation for this enigma, whereby TLR7 and TLR9 experience a surprising degree of differential regulation, both at the level of receptor trafficking as well as receptor activation in the endosome. Although his work provides a major conceptual advance for explaining the distinct behavior of these two receptors in disease, we still poorly understand how the regulation of nucleic acid-sensing TLRs and its various interactions and pathways are embedded into the cellular architecture. Their cellular location is not trivial: knowing where in the cell these critical interactions take place and how they are coordinated in time is of utmost importance to fully understand how TLRs are regulated to avoid self-recognition. In this project, the fellow aims to investigate these fundamental aspects of TLR biology using state-of-the art superresolution microscopy. He will use sub-diffraction imaging techniques including stochastic optical reconstruction microscopy (STORM) and Airyscanning technology to 1) define the precise subcellular localization of nucleic acid-sensing TLRs, 2) identify and characterize their endosomal signaling compartments, and 3) investigate TLR signaling dynamics under normal and autoimmune-prone conditions. This work will provide a conceptual framework for understanding how TLR signaling is controlled in space and time and define the molecular principles that maintain self-tolerance to nucleic acids.