The preclinical development of cationic antimicrobial peptides as an alternative to antibiotics is precluded, among other processes, by their inactivation by salts. Taking inspiration from marine biodiversity, our goal is to turn salt-sensitive human defensins into salt-stable defensins. This ambitious goal is made possible thanks to (i) recent discoveries from our consortium on the structure/activity of big-defensins, the marine ancestors of vertebrate ß-defensins (ii) new methodologies in chemical synthesis and engineering of such molecules, and (iii) the multidisciplinary team gathered in the MOSAR-Def consortium that brings together peptide chemists, biochemists, structural biologists, microbiologists (marine and human) and cell physiolgists. The project will contribute to significant knowledge on the mechanisms of defensins active both at normal and high salt concentrations, and their therapeutic applications. This represents a step further to unravel alternatives to conventional antibiotics treatments.
Project Funded by the ANR (ANR-19-CE18-0025)
CURRENT PROJECTS
MOSARDEF. How to MOdulate the SAlt-stability of antimicRobial DEFensins
PI : Agnès Delmas (CBM Orléans)
Collaborators: Vincent Aucagne, Karine Loth, Hervé Meudal, Lhousseine Touqui, Philippe Bulet, Sébastien Voisin, Rafael Da Rosa, Noémie de San Nicolas, Caroline Montagnani, Jean-Michel Escoubas, Viviane Boulo, Guillaume Charrière, Delphine Destoumieux-Garzon
SPARE-SEA: Environmental Spread and Persistence of Antibiotic REsistances in aquatic Systems Exposed to oyster Aquaculture
PI : Mathias Wegner (AWI, Germany)
Collaborators : Luigi Vezzuli (UNIGE, Italy), Gianlucca Como (CNR, Italy), Karl Andree and Dolors Furones (IRTA, Spain), Delphine Destoumieux-Garzon, Caroline Montagnani, Eve Toulza, Céline Cosseau, Arnaud Lagorce, Viviane Boulo, Marie-Agnès Travers, Gaelle Courtay, and Océane Romatif (IHPE, France), Bruno Petton and Fabrice Pernet (LEMAR, France)
Aquaculture has been identified as a gateway for antibiotic resistance (AR) spread, but little is known of AR in the oyster aquaculture environment. Antibiotics are used in hatcheries, and since oysters enrich bacteria, consumption of raw oysters can be a vector for AR into human microbiomes. AR therefore threatens the safety of coastal marine systems, the sustainability of shellfish farming and human health. By combining human, animal and environmental health, SPARE-SEA implements a One Health approach to identify environmental drivers of AR spread within and between environmental compartments including known and emerging pathogens. By investigating the cumulative effects of human use of coastal ecosystems along multiple gradients including proximity to oyster farms and agrochemical pollutant run-off on the enrichment of AR in the oyster bio-reactor, we will link objectives of all three JPIs involved and determine the future research lines in the field of AR in bivalve aquaculture.
Funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 869178-AquaticPollutants.
Funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 869178-AquaticPollutants.
TRANSCAN: Ecology and evolution of transmissible cancers
PI : Frédéric THOMAS (MIVEGEC, France)
Collaborators: Beata Ujvari (Deakin University, Australia), Rodrigo Hamede (University of Tasmania), Benjamin Roche (MIVEGEC Montpellier), Nicolas Bierne (ISEM, Montpellier), Delphine Destoumieux-Garzon (CNRS, Montpellier), Guillaume Charrière (Université de Montpellier), Maurine Hammel (Université de Montpellier), Erika Burioli (CNRS, Montpellier).
Transmissible cancers are one of the most intriguing and unexplored host-pathogen systems. The pathogen is a clonal infectious malignant cell line, a rogue cell type that has derived and deviated directly from the host or from a closely related species. While the ultimate fate of malignant cells is usually to expire with the death of the host, evolutionary theory postulates that cancer cell lineages that are able to become transmissible (hence escape the demise of their host) will acquire higher fitness, and consequently be favoured by selection. Once the neoplastic process has crossed the threshold of contagiousness, malignant cells become new parasitic “species”. Currently, eight transmissible cancers (one lineage in dogs, two lineages in Tasmanian devils, and five lineages in four bivalve species), have been recorded in the wild, but their real abundance has most likely been underestimated. Transmissible cancers are a rare type of natural enemy but their ecological consequences can be major (e.g. > 85% population decline in 20 years in Tasmanian devils; epizootic outbreaks in marine mollusk populations). Altogether, the increasing number of case reports is raising major questions: Why do transmissible cancers emerge? How do they evolve? What are their ecological and evolutionary impacts and how to manage them? In this proposal, we wish to address these questions by exploring two contrasted and complementary host/transmissible cancer associations (i.e. vertebrate/invertebrate hosts, presence/absence of motile infective stages, different levels of host specificity) through a multidisciplinary approach.
Project funding: ANR TRANSCAN (ANR-18-CE35-0009) 2019-2023
Read moreProject funding: ANR TRANSCAN (ANR-18-CE35-0009) 2019-2023
RELEVANT PUBLICATIONS Click here for the full list
Species-specific mechanisms of cytotoxicity toward immune cells determine the successful outcome of Vibrio infections
Rubio T., Oyanedel-Trigo D., Labreuche Y., Toulza E., Luo X., Bruto M., Chaparro C., Torres M., de Lorgeril J, Haffner P., Vidal-Dupiol J., Lagorce A., Petton B., Mitta G., Jacq A., Le Roux F., Charrière G. and Destoumieux-Garzón D (2019)
Proc Natl Acad Sci U S A,
Vibrio species cause infectious diseases in humans and animals, but they can also live as commensals within their host tissues. How Vibrio subverts the host defenses to mount a successful infection remains poorly understood, and this knowledge is critical for predicting and managing disease. Here, we have investigated the cellular and molecular mechanisms underpinning infection and colonization of 2 virulent Vibrio species in an ecologically relevant host model, oyster, to study interactions with marine Vibrio species. All Vibrio strains were recognized by the immune system, but only nonvirulent strains were controlled. We showed that virulent strains were cytotoxic to hemocytes, oyster immune cells. By analyzing host and bacterial transcriptional responses to infection, together with Vibrio gene knock-outs, we discovered that Vibrio crassostreae and Vibrio tasmaniensis use distinct mechanisms to cause hemocyte lysis. Whereas V. crassostreae cytotoxicity is dependent on a direct contact with hemocytes and requires an ancestral gene encoding a protein of unknown function, r5.7, V. tasmaniensis cytotoxicity is dependent on phagocytosis and requires intracellular secretion of T6SS effectors. We conclude that proliferation of commensal vibrios is controlled by the host immune system, preventing systemic infections in oysters, whereas the successful infection of virulent strains relies on Vibrio species-specific molecular determinants that converge to compromise host immune cell function, allowing evasion of the host immune system.
Proc Natl Acad Sci U S A,
Vibrio species cause infectious diseases in humans and animals, but they can also live as commensals within their host tissues. How Vibrio subverts the host defenses to mount a successful infection remains poorly understood, and this knowledge is critical for predicting and managing disease. Here, we have investigated the cellular and molecular mechanisms underpinning infection and colonization of 2 virulent Vibrio species in an ecologically relevant host model, oyster, to study interactions with marine Vibrio species. All Vibrio strains were recognized by the immune system, but only nonvirulent strains were controlled. We showed that virulent strains were cytotoxic to hemocytes, oyster immune cells. By analyzing host and bacterial transcriptional responses to infection, together with Vibrio gene knock-outs, we discovered that Vibrio crassostreae and Vibrio tasmaniensis use distinct mechanisms to cause hemocyte lysis. Whereas V. crassostreae cytotoxicity is dependent on a direct contact with hemocytes and requires an ancestral gene encoding a protein of unknown function, r5.7, V. tasmaniensis cytotoxicity is dependent on phagocytosis and requires intracellular secretion of T6SS effectors. We conclude that proliferation of commensal vibrios is controlled by the host immune system, preventing systemic infections in oysters, whereas the successful infection of virulent strains relies on Vibrio species-specific molecular determinants that converge to compromise host immune cell function, allowing evasion of the host immune system.
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Read moreNEWS
We are recruiting for a post-doctoral position starting Octobre 2021
Aquaculture has been identified as a gateway for antimicrobial resistance (AMR) spread worldwide. Still, little is known on AMR in the oyster aquaculture environment. The economically important oyster species Crassostrea gigas is cultured in coastal areas that are often contaminated by AMR determinants (antibiotics, resistance genes, and resistant bacteria) and other pollutants known to co-select for AMR. Moreover, antibiotics are used in hatcheries. AMR therefore threatens the safety of coastal marine systems, the sustainability of shellfish farming and human health. Preliminary data obtained at the IHPE lab have shown that antibiotic-resistance genes (ARG) are present in the genomes of oyster-associated vibrios (Rubio T et al, PNAS, 2019 ; Lagorce A et al., non publié) and are expressed by the oyster-associated microbiota (metatranscriptomic data) (Lucasson A et al., BioRxiv, 2020). A first inventory has evidenced a broad diversity of ARG circulating in Vibrio isolated from coastal environments used for oyster culture (unpublished). The post-doctorate is part of the European SPARE-SEA project aimed at characterizing the environmental spread and persistence of antibiotic resistances in aquatic systems use for oyster farming. The objective of the postdoctoral researcher will be (i) to estimate ARG occurrence and expression in microbiota of oysters sampled along anthropization gradients using metatranscriptomics analysis and (ii) to identify potential human/environmental drivers of ARG selection in coastal marine environments through statistical analysis. The study will be conducted in four European regions used for oyster farming.
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PHOTO GALLERY
Centre for Research on the Ecology and Evolution of DiseaSes
Montpellier
Montpellier