Timing malaria transmission with mosquito fluctuations.

Temporal variations in the activity of arthropod vectors can dramatically affect the epidemiology and evolution of vector-borne pathogens. Here, we explore the "Hawking hypothesis", which states that these pathogens may evolve the ability to time investment in transmission to match the activity of their vectors. First, we use a theoretical model to identify the conditions promoting the evolution of time-varying transmission strategies in pathogens. Second, we experimentally test the "Hawking hypothesis" by monitoring the within-host dynamics of <i>Plasmodium relictum</i> throughout the acute and the chronic phases of the bird infection. We detect a periodic increase of parasitemia and mosquito infection in the late afternoon that coincides with an increase in the biting activity of its natural vector. We also detect a positive effect of mosquito bites on <i>Plasmodium</i> replication in the birds both in the acute and in the chronic phases of the infection. This study highlights that <i>Plasmodium</i> parasites use two different strategies to increase the match between transmission potential and vector availability. We discuss the adaptive nature of these unconditional and plastic transmission strategies with respect to the time scale and the predictability of the fluctuations in the activity of the vector

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

Circadian Control of Antibacterial Immunity: Findings from Animal Models

International audienceMost of the biological functions, including the immune system, are linked to circadian rhythms in living organisms. Changes occurring to biological parameters as the result of these circadian rhythms can therefore affect the outcome of a disease. For decades, model organisms have proven to be a great tool to understanding biological mechanisms such as circadian cycle and immunity. In this review, we created an inventory of the use of model organisms in order to decipher the relation between circadian rhythms and antibacterial immunity

The trained immunity in invertebrates What do we know?

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Conformational Insights into the Control of CNF1 Toxin Activity by Peptidyl-Prolyl Isomerization: A Molecular Dynamics Perspective

International audienceThe cytotoxic necrotizing factor 1 (CNF1) toxin from uropathogenic Escherichia coli constitutively activates Rho GTPases by catalyzing the deamidation of a critical glutamine residue located in the switch II (SWII). In crystallographic structures of the CNF1 catalytic domain (CNF1CD), surface-exposed P768 and P968 peptidyl-prolyl imide bonds (X-Pro) adopt an unusual cis conformation. Here, we show that mutation of each proline residue into glycine abrogates CNF1CD in vitro deamidase activity, while mutant forms of CNF1 remain functional on RhoA in cells. Using molecular dynamics simulations coupled to protein-peptide docking, we highlight the long-distance impact of peptidyl-prolyl cis-trans isomerization on the network of interactions between the loops bordering the entrance of the catalytic cleft. The energetically favorable isomerization of P768 compared with P968, induces an enlargement of loop L1 that fosters the invasion of CNF1CD catalytic cleft by a peptide encompassing SWII of RhoA. The connection of the P968 cis isomer to the catalytic cysteine C866 via a ladder of stacking interactions is alleviated along the cis-trans isomerization. Finally, the cis-trans conversion of P768 favors a switch of the thiol side chain of C866 from a resting to an active orientation. The long-distance impact of peptidyl-prolyl cis-trans isomerizations is expected to have implications for target modification

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