Deciphering planarians resistance mechanims against bacteria

Les planaires sont des plathelminthes d'eau douce non parasitaires qui ont été intensément étudiés pour leurs capacités exceptionnelles de régénération. En 2014, Abnave et ses collaborateurs ont démontré la capacité de Dugesia japonica, une espèce de planaire, à résister aux bactéries pathogènes pour l’homme et pour d’autres organismes modèles. Grâce à l’utilisation de techniques transcriptomiques et de criblage par ARN interférence, l’implication du gène Morn-2 dans cette résistance aux bactéries a été démontrée et l’étude de Morn-2 dans les macrophages humains a permis d’identifier son rôle dans la LAP (LC3 Associated Phagocytosis) autophagie ; Les planaires peuvent donc servir de modèle pour la découverte d’autres mécanismes de résistance conservés chez l’homme. Cependant, la réponse immunitaire des planaires a jusqu’ici été très peu explorée. Ce travail a été entrepris en vue d’identifier et de caractériser les mécanismes mis en jeu par ce modèle pour répondre efficacement aux bactéries. Dans une première partie de ce travail, il est démontré que les planaires possèdent une mémoire immunitaire innée spécifique à Staphylococcus aureus. Ensuite l’influence du rythme circadien sur la réponse antibactérienne des planaires a été examinée. Pour finir, l’intérêt s’est porté sur les mécanismes de reconnaissance et d’activation de la réponse antibactérienne chez les planaires. En dépit de l’absence de récepteurs Toll Like Receptor (TLR) chez les planaires, il est montré que des gènes homologues aux gènes de la voie de signalisation TLR des mammifères sont présents chez ces derniers.Planarians are freshwater flatworms that have been intensively studied for their regenerative capacities. These non-parasitic Platyhelminthes are in their natural aquatic environment perpetually in contact with dense and diverse microbial population. Planarians have recently attracted broad attention owing to the discovery of innate immune regulators conserved in humans but absent in other classical model organisms. Notably, Abnave and collaborators highlighted the ability of Dugesia japonica and Schmidtea mediterranea of resisting to pathogenic bacteria by mean of Morn2-dependent LC3-associated phagocytosis. However, critical questions remain about mechanisms conferring a resistance of planarians to pathogenic bacteria as well as their mode of perception of PAMPs. In this work we explored different components of planarians immune system. First, we demonstrated the existence in planarians of an innate immune memory that is specific to Staphylococcus aureus. Second, we investigated the role of the circadian machinery in the anti-bacterial response. Surprisingly, classical Toll Like receptors (TLRs) are absent in planarians despite their wide conservation in the animal kingdom. We found genes in planarians showing similarities with mammalian TLR signalling components. Moreover, we report the landscape of TIR-domain containing proteins in planarians and discuss their function and evolution with regard to known TLR-signalling components

La mémoire immunitaire entraînée chez les invertébrés

L’un des mécanismes de défense de l’hôte consiste en l’immunité entraînée, composante de l’immunité innée, également connue sous le nom de mémoire immunitaire innée. La mémoire immunitaire innée est définie comme une protection exacerbée d’un organisme lors d’un deuxième contact avec un corps étranger, comme un micro-organisme pathogène. Il s’agit d’une immunité qui ne fait pas intervenir les composants de l’immunité acquise, comme les lymphocytes B ou les lymphocytes T. Elle repose essentiellement sur la machinerie cellulaire et moléculaire de la réponse innée. La mémoire immunitaire innée a été décrite aussi bien chez les invertébrés et que les vertébrés, mais son mécanisme ne commence à être élucidé que depuis récemment, en particulier chez les vertébrés. La plupart des recherches sur la mémoire immunitaire innée repose, aujourd’hui, sur des modèles vertébrés, oubliant que ce mécanisme existe également chez les invertébrés. Pourtant, les invertébrés présentent l’avantage de pouvoir étudier la mémoire immunitaire dans des modèles qui sont naturellement dépourvus d’immunité acquise. L’objectif de cette revue est donc de réaliser un point sur la mémoire immunitaire innée des invertébrés

The trained immunity in invertebrates What do we know?

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In silico analysis of Schmidtea mediterranea TIR domain-containing proteins

International audienceWhile genetic evidence points towards an absence of Toll-Like Receptors (TLRs) in Platyhelminthes, the Toll/IL-1 Receptor (TIR)-domains that drive the assembly of signalling complexes downstream TLR are present in these organisms. Here, we undertook the characterisation of the repertoire of TIR-domain containing proteins in Schmidtea mediterranea in order to gain valuable information on TLR evolution in metazoan. We report the presence of twenty proteins containing between one and two TIR domains. In addition, our phylogenetic-based reconstruction approach identified Smed-SARM and Smed-MyD88 as conserved TLR adaptors. (C) 2018 Elsevier Ltd. All rights reserved

Antimicrobial capacity of the freshwater planarians against S-aureus is under the control of Timeless

International audiencePlanarians, which are non-parasitic flatworms, are highly resistant to bacterial infections. To better understand the mechanisms underlying this resistance, we investigated the role of the circadian machinery in the anti-bacterial response of the freshwater planarian Schmidtea mediterranea. We identified Smed-Tim from S. mediterranea as a homolog of the mammalian clock gene Tim. We showed via RNA interference that Smed-Tim is required for the antimicrobial activities of Schmidtea mediterranea against Staphylococcus aureus infection during the light/dark cycle. Indeed, S. aureus infection leads to the expression of Smed-Tim, which in turn promotes Smed-Traf6 and Smed-morn2, but not Smed-p38 MAPK expression, 2 master regulators of planarian anti-microbial responses

Staphylococcus aureus Promotes Smed-PGRP-2/Smed-setd8-1 Methyltransferase Signalling in Planarian Neoblasts to Sensitize Anti-bacterial Gene Responses During Re-infection

International audienceLittle is known about how organisms exposed to recurrent infections adapt their innate immune responses. Here, we report that planarians display a form of instructed immunity to primo-infection by Staphylococcus aureus that consists of a transient state of heightened resistance to re-infection that persists for approximately 30 days after primo-infection. We established the involvement of stem cell-like neoblasts in this instructed immunity using the complementary approaches of RNA-interference-mediated cell depletion and tissue grafting-mediated gain of function. Mechanistically, primo-infection leads to expression of the peptidoglycan receptor Smed-PGRP-2, which in turn promotes Smed-setd8-1 histone methyltransferase expression and increases levels of lysine meth-ylation in neoblasts. Depletion of neoblasts did not affect S. aureus clearance in primo-infection but, in re-infection , abrogated the heightened elimination of bacteria and reduced Smed-PGRP-2 and Smed-setd8-1 expression. Smed-PGRP-2 and Smed-setd8-1 sensitize animals to heightened expression of Smed-p38 MAPK and Smed-morn2, which are downstream components of anti-bacterial responses. Our study reveals a central role of neoblasts in innate immunity against S. aureus to establish a resistance state facilitating Smed-sted8-1-dependent expression of anti-bacterial genes during re-infection

The cnf1 gene is associated to an expanding Escherichia coli ST131 H30Rx/C2 sublineage and confers a competitive advantage for host colonization

Epidemiological projections point to acquisition of ever-expanding multidrug resistance (MDR) by Escherichia coli, a commensal of the digestive tract acting as a source of urinary tract pathogens. We performed a high-throughput genetic screening of predominantly clinical E. coli isolates from wide geographical origins. This revealed a preferential distribution of the Cytotoxic Necrotizing Factor 1 (CNF1)-toxin encoding gene, cnf1, in four sequence types encompassing the pandemic E. coli MDR lineage ST131. This lineage is responsible for a majority of extraintestinal infections that escape first-line antibiotic treatment and has known enhanced capacities to colonize the gastrointestinal tract (GIT). Statistical modeling uncovered a dominant global expansion of cnf1-positive strains within multidrug-resistant ST131 subclade H30Rx/C2. Despite the absence of phylogeographical signals, cnf1-positive isolates adopted a clonal distribution into clusters on the ST131-H30Rx/C2 phylogeny, sharing a similar profile of virulence factors and the same cnf1 allele. Functional analysis of the cnf1-positive clinical strain EC131GY ST131-H30Rx/C2, established that a cnf1-deleted EC131GY is outcompeted by the wildtype strain in a mouse model of competitive infection of the bladder while both strains behave similarly during monoinfections. This points for positive selection of cnf1 during UTI rather than urovirulence. Wildtype EC131GY also outcompeted the mutant when concurrently inoculated into the gastrointestinal tract, arguing for selection within the gut. Whatever the site of selection, these findings support that the benefit of cnf1 enhancing host colonization by ST131-H30Rx/C2 in turn drives a worldwide dissemination of the cnf1 gene together with extended spectrum of antibiotic resistance genes