Système immunitaire inné | EPFL Graph Search

vignette|Schéma simplifié de l'homéostasie et de la réponse immunitaire au niveau de la barrière intestinale. Le système immunitaire inné comprend les cellules et les mécanismes permettant la défense immédiate de l'organisme contre les agents infectieux de façon immédiate car elle ne nécessite pas de division cellulaire. Il s'oppose en cela au système immunitaire adaptatif, qui confère une protection plus tardive mais plus durable, et qui nécessite une division cellulaire (lymphocyte B et T). Bien que cette défense ne soit pas spécifique d'une espèce particulière d'agent pathogène, elle peut reconnaître des types de pathogènes, comme par exemple les bactéries Gram négatif qui sont reconnues par les récepteurs appelés pattern recognition receptor (PRR) ou en français récepteur de reconnaissance de motifs moléculaires. Alors que le système immunitaire adaptatif existe uniquement chez les gnathostomes, le système immunitaire inné existe dans tous les organismes du règne végétal et anim

Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signalling

Andrea Ablasser, Ensieh Farahani, Alix Martin, Bing Zhang

The innate immune system is crucial for eventual control of infections, but may also contribute to pathology. Listeria monocytogenes is an intracellular Gram-positive bacteria and a major cause of food-borne disease. However, important knowledge on the interactions between L. monocytogenes and the immune system is still missing. Here, we report that Listeria DNA is sorted into extracellular vesicles (EVs) in infected cells and delivered to bystander cells to stimulate the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway. This was also observed during infections with Francisella tularensis and Legionella pneumophila. We identify the multivesicular body protein MVB12b as a target for TANK-binding kinase 1 phosphorylation, which is essential for the sorting of DNA into EVs and stimulation of bystander cells. EVs from Listeria-infected cells inhibited T-cell proliferation, and primed T cells for apoptosis. Collectively, we describe a pathway for EV-mediated delivery of foreign DNA to bystander cells, and suggest that intracellular bacteria exploit this pathway to impair antibacterial defence.

NATURE PUBLISHING GROUP2019

Exploring the mechanisms governing nuclear cGAS localization and activity

Marilena Wischnewski

Recognition of pathogen-derived molecules through germline-encoded receptors is a fundamental principle of innate immunity. Pattern recognition receptors detect specific intracellular danger signals to trigger potent immune responses. The DNA sensor cyclic GMP-AMP synthase (cGAS) detects double-stranded DNA derived from viruses and microbes in the cytoplasm. However, due to its ability to recognize DNA independent of sequence, aberrant detection of self-DNA in various settings can lead to autoinflammatory diseases. Under physiological conditions, genomic DNA is sequestered in the nucleus and shielded from cytosolic molecules by the nuclear envelope (NE). Nevertheless, cGAS gains access to the nuclear compartment in some instances, and the mechanisms controlling its activity on genomic DNA are not fully known.In this study, we investigate the regulation of nuclear cGAS localization and activity in different contexts. We first describe how cGAS activity against nuclear DNA is restricted in instances of spontaneous loss of nucleo-cytoplasmic compartmentalization. Upon NE rupture, cGAS enters the nucleus, but is prevented from activation by Barrier-to-autointegration factor 1 (BAF). BAF dynamically competes with cGAS for DNA binding, thereby preventing the formation of stable cGAS-DNA complexes and cGAS enzymatic activity. We thus identify a cellular safeguard mechanism, beyond physical separation, that restricts cGAS activity against genomic self-DNA.In addition, we investigate cGAS activation in conditions associated with a disrupted NE. Instability of the NE is a hallmark of laminopathies, diseases of the nuclear lamina that can manifest in premature aging phenotypes. While we find no contribution of basal cGAS signaling to the pathogenesis of two different progeria syndromes, we detect a decreased capacity to respond to DNA challenge on the cellular level, suggesting that cGAS may be sequestered inside the nucleus in these cells.Lastly, because cGAS is increasingly recognized to reside inside the nucleus at steady state, we delineate cGAS nuclear localization in time and space. In cycling cells, nuclear cGAS levels oscillate with the cell cycle and are highest after mitosis followed by a sharp decrease in G1 phase. We report that cGAS is not exported during G1, but rather subjected to degradation inside the nucleus by the nuclear proteasome. Moreover, we establish a technique to study potential interaction partners of nuclear cGAS, which opens up intriguing possibilities for further investigation.Together, our findings contribute to a better understanding of the regulatory processes that govern nuclear cGAS localization and activity, and will help to uncover potential disease-causing aberrations in the future.

EPFL2022

An unexpected role for RNA in the recognition of DNA by the innate immune system

Andrea Ablasser

A central function of our innate immune system is to sense microbial pathogens through the presence of their nucleic acid genomes or their transcriptional or replicative activity. In mammals, a receptor-based system is mainly responsible for the detection of these "non self" nucleic acids. Tremendous progress has been made in the past years in identifying the host constituents that are required for this intricate task. With regard to the sensing of RNA genome based pathogens by our innate immune system, a picture is emerging that includes certain families of the toll-like receptor family (TLR3, TLR7, TLR8) and the RIG-I like helicases (RIG-I, MDA5 and LGP2). Genetic loss of function studies implicate that the absence of these pathways can lead to a complete lack of recognition of certain RNA viruses. At the same time, intracellular DNA can also trigger potent innate immune responses, yet the players in this field are less clear. We and another group have recently identified a role for RNA polymerase III in the conversion of AT-rich DNA into an RNA ligand that is sensed by the RIG-I pathway. In this review article, we will discuss the mechanisms and implications of this novel pathway.

2010

Exploring the mechanisms governing nuclear cGAS localization and activity

Marilena Wischnewski

EPFL2022