H2020Индивидуална стипендия2019–2021

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

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2019-07-01 → 2021-06-30
Финансиране от ЕС: 162 806 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Имунните рецептори TLR7, TLR8 и TLR9 се разполагат в клетката така, че да разпознават чужди нуклеинови киселини и да игнорират собствените ни. Разбирането на този механизъм помага да се обяснят причините за развитието на автоимунни и автоинфламаторни заболявания.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

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

This project aimed to understand how the regulation of nucleic acid-sensing Toll-like receptors (TLRs) and its various interactions are integrated into the cellular architecture. It has long been appreciated that the endosomal localization of this class of immune receptors is critical for proper self/non-self discrimination of nucleic acids, and that the breakdown of this compartmentalization can lead to autoimmune or autoinflammatory diseases. Here, I proposed to elucidate the spatial and functional segregation of endosomal TLRs to systematically dissect how their subcellular distribution impacts signaling and maintains immune tolerance. The dysregulation of nucleic acid-sensing TLRs, including TLR7, TLR8, and TLR9, is known to play a major role in numerous human autoimmune diseases. Interestingly, the cellular mechanisms that promote loss of self-tolerance by individual TLRs seem to differ. For example, while overexpression of TLR7 is sufficient to break the ‘tolerance’ mechanisms that normally prevent reactivity to self, merely increasing the number of TLR9 molecules in the cell does not lead to aberrant activation of TLR9. These findings point to fine-tuned regulation of each TLR family member, the details of which are only recently coming to light. Thus, the differential regulation of nucleic acid-sensing TLRs is of medical relevance for understanding the pathomechanisms of autoimmunity and autoinflammatory disease. This work will provide a conceptual framework for how TLR signaling is controlled in space and time and define the molecular principles that maintain self-tolerance to nucleic acids. The formal objectives of this MSCA have been to 1) define the precise subcellular localization (single-molecule resolution) of nucleic acid-sensing TLRs, to 2) identify and characterize the intracellular TLR signaling compartments, and to 3) investigate TLR signaling dynamics under normal and dysregulated (autoimmune-prone) conditions. The fellowship has been prematurely suspended as I accepted a Research Group Leader position at the Max Planck Institute for Infection Biology (MPIIB) in Berlin. I will continue to explore the same research questions in my own laboratory.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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. My 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 my 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, I aim to investigate these fundamental aspects of TLR biology using state-of-the art superresolution microscopy. I 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.

Оригинален текст от CORDIS (на английски).

Участници

FREIE UNIVERSITAET BERLIN · BerlinКоординаторГермания