HAL ENVT (Ecole Nationale Vétérinaire de Toulouse)
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P-glycoprotein-9-mediated multidrug tolerance in Caenorhabditis elegans
No full textInternational audienceBackground The active drug efflux pumps P-glycoproteins (PGPs) are the cornerstones of multidrug resistance in many organisms. In parasitic helminths, resistance to macrocyclic lactones (MLs) has been associated with pgp regulation and structural defects in amphids. In Caenorhabditis elegans , the nuclear hormone receptor (NHR)-8 also influences xenobiotic tolerance by regulating pgp genes. However, the specific contribution of individual transporters and their regulation remain poorly defined. We recently demonstrated that PGP-9 specifically contributes to ivermectin (IVM) tolerance in an IVM-resistant C. elegans strain. This study aimed to explore the role of PGP-9 in drug efflux in C. elegans . Methods We used the IVM-resistant and dye-filling defective (Dyf) C. elegans strain IVR10 and a pgp-9 IVR10 mutant to assess larval development under MLs (eprinomectin (EPR) and moxidectin (MOX)) and tunicamycin (TM). We evaluated whether the Dyf phenotype was affected by pgp-9 deletion. We investigated the role of NHR-8 in regulating pgp-9 via reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and by assessing ML sensitivity in an IVR10 nhr-8 mutant. Additional candidate regulators of pgp-9 were also tested. Results IVR10 displayed resistance to MLs and to TM, while pgp-9 deletion restored full drug sensitivity despite the persistence of the Dyf phenotype. Although nhr-8 deletion in IVR10 increased IVM sensitivity, pgp-9 expression was not significantly altered in that strain or IVR10. Interfering RNA (RNAi) targeting pgp-9 in the nhr-8 mutant further increased IVM sensitivity, uncoupling PGP-9 from NHR-8 regulation. Candidate NHRs did not affect IVM tolerance in N2B. Conclusions These results provide the first direct evidence that PGP-9 is necessary for multidrug tolerance in C. elegans , independently of amphid structural defects and NHR-8 regulation. These findings uncover a novel mechanism supporting drug resistance and highlight PGP-9 as a potential therapeutic target to improve ML treatments
Proteases in intestinal health and disease
No full textInternational audienceExtracellular proteases, originating from the host or the microbiota, are key signalling molecules involved in cellular communication with the environment. They signal through a wide array of mechanisms, ranging from receptor activation to protein transformation and even degradation. Protease signals are irreversible, as it involves the cleavage of proteins. Therefore, proteases are tightly controlled, and must be understood within the context of the complex networks in which they operate - their activity is tightly regulated by access to specific substrates and the presence of inhibitors. The intestine is particularly exposed to extracellular proteases, which have major roles in gut physiology: digestion, food antigen processing, barrier function, epithelial renewal and microbiome homeostasis. Dysregulated proteolytic balance is associated with intestinal pathologies including inflammatory bowel disease, irritable bowel syndrome, coeliac disease and colorectal cancer. Extracellular proteases are major contributors to a number of gut dysfunctions, including microbiota dysbiosis, barrier dysfunction, matrix remodelling, activation of mucosal immunity and nociceptive or motility abnormalities. Consequently, proteolytic homeostasis at the intestinal mucosa surface has become a goal for intestinal health, and new therapeutic options targeting the interplay among proteases, their inhibitors and their substrates have been explored
Establishing reference values and evaluating analytical approaches for plasma vitamin E in dogs
No full textInternational audienceIntroduction: In humans, vitamin E status is assessed by the ratio of plasma vitamin E to total lipids (cholesterol + triglycerides) [1]. There is no consensus on the best method to analyse vitamin E in dogs, with various approaches (e.g., total vitamin E or vitamin E/total lipids) appearing in the literature. Additionally, reference values for dogs are lacking. This study aimed to compare plasma total vitamin E with vitamin E normalized to total lipids and to establish reference values.Animals, material and methods: A total of 106 owner-reported healthy dogs (>20 kg) were recruited voluntarily for a free check-up, including 50 young (2–5 years) and 56 senior (>8 years) dogs. The dogs received 4 weeks of the same premium diet. Clinical variables, hematology and plasma biochemistry were recorded, and vitamin E (α-tocopherol) was assayed with HPLC adapted from [2]. Hair quality was evaluated by a veterinarian using a published scoring system [3]. Owners completed a detailed health and dietary form based on WSAVA guidelines [4]. Seven dogs (4 seniors, 3 young) were excluded as they did not meet established health criteria [5]. Associations between plasma total vitamin E or the vitamin E:total lipids ratio and other parameters (pre-selected via PLS-DA) were analyzed using linear regression with forward and backward stepwise selection. P-values were obtained using Type III ANOVA in R 4.2.2.Results: The 95% reference interval for total plasma vitamin E was [14,36] µg/mL, and [0.5,1.5] mg/g for the plasma vitamin E:total lipids ratio. Total cholesterol was the only parameter positively associated with total plasma vitamin E (Table 1). Neutering, consumption of non-commercial foods before challenge, and plasma glucose were negatively associated with vitamin E:total lipids ratio, red blood cell count (RBC) showed a positive association (Table 2).Discussion and conclusion: This study provides the first reference intervals for plasma total vitamin E and the vitamin E:total lipids ratio in healthy adult and senior dogs. The positive association between total cholesterol and plasma vitamin E highlights the influence of lipid levels on vitamin E status, in accordance with human studies. Conversely, the vitamin E:total lipids ratio was influenced by non-lipid factors, suggesting it may better reflect oxidative status independent of lipid concentrations. These results underscore the need for standardized methods when using vitamin E as a biomarker in canine oxidative stress research. References: [1] Traber (2014) in Modern nutrition in health and disease, p293-304; [2] Lyan (2001) J of Chromatography p297-230; [3] Devriendt (2021) in Vlaams Diergeneeskundig Tijdschrift, p227-230, [4] WSAVA (2011) J Small An Pract p385-396; [5] Schooley (2024), SSRN, abstract 5010477
Deciphering the mode of action of bioinspired lipidic compounds as promising antituberculosis drugs
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Safeguarding a local breed of pig through the Noir de Bigorre value chain
No full textThe agrifood sector encountered increasing market segmentation, with the proliferation of public and private quality claims (i.e. labels), which commit the supply chains to the building of differentiated production, processing and distribution practices. We know very little about the way in which value chains move towards agroecology, particularly for value chains with quality labels other than organic farming. From 2022 to 2023, INRAE’s Scientific Division for Agriculture conducted an exploratory project with 11 sector research groups of INRAE to analyse how differentiated supply chains are committing to agroecology. This project, entitled ‘Agroecology and Market’, was based on desk research and interviews with over 60 actors from the interbranch organisations and different stages in agrifood chains. This introductory article presents the rationale for the project, the mission of the INRAE sector research groups and the 28 case studies selected for illustrative purposes in order to conduct this exploratory analysis in a diverse range of production and supply chain contexts.International audienceAlthough French pork production is considered to be relatively homogeneous, a range of products from alternative breeding systems including, among others, official quality labels, has been developed. The example of the Noir de Bigorre chain, based on the preservation and promotion of the Gascon pig breed, can shed light on the development of an initiative whose principles largely correspond with the elements of agroecology proposed by the Food and Agriculture Organization (FAO). When interviewed about their organisation, the representatives of this pork chain and a processing partner largely identified with these different dimensions of agroecology. The founding principle shared by all is that of human and social values and although based on the enhancement of ancestral practices, the success of this chain is based on numerous technical and organisational innovations
CAGES OU PARCS AVEC JARDIN d'HIVER : EFFET DES CONDITIONS DE LOGEMENT SUR LE COMPORTEMENT, LE STRESS ET LES PERFORMANCES DE LAPINS EN CROISSANCE
No full textInternational audienceLa société est préoccupée par le bien-être des lapins de chair. Il est fortement influencé par les conditions de vie. Nous avons comparé le bien-être (comportement et stress), la croissance et la viabilité de 60 lapins (♀ Hycole x ♂ PS119 Hypharm), élevés dans deux conditions de logement différentes de 38 (sevrage) à 70 jours : cages standard (groupe Cage) versus parc avec jardin d'hiver (système Wellap®) (groupe Parc). Les animaux ont été pesés à 38j et à 70j. Le comportement a été mesuré par scan sampling à 48 et 70 jours d’âge selon un éthogramme simple. La corticostérone a été dosée dans le poil à 70j par une méthode Elisa en immunocompétition. La croissance a été plus élevée dans le groupe parc (2,75 kg contre 2,46 kg à 70 jours, P < 0,01), la viabilité était similaire pour les deux conditions de logement (97 % contre 97,5 %, NS). Les niveaux de corticostérone dans les poils à 70 jours avaient tendance à être plus élevés dans le groupe Parc que dans le groupe Cage (2,48 vs 1,76 pg/mg de poils, P= 0,08). Dans le groupe Parc, les lapins étaient plus actifs et exprimaient plus de comportements d'exploration (marcher, courir, se cabrer) et plus de comportements de toilettage alors que dans le groupe Cage, les lapins se reposaient plus et avaient plus d'interactions de contact (P < 0.05). L'accès à un jardin d’hiver a permis aux lapins d'avoir un répertoire comportemental plus riche. En conclusion, les présents résultats montrent que l'accès à un jardin d’hiver pourrait être une bonne solution pour améliorer le bien-être des lapins, en diversifiant le répertoire comportemental et en augmentant la croissance sans augmenter le stress ou réduire la viabilité des animaux
Corrélations entre la personnalité du propriétaire et le profil comportemental du chien : vers une optimisation du processus d’adoption
No full textThis study aims to identify combinations of human personality traits and canine temperament that promote a harmonious relationship, in order to reduce adoption failures. Using the Big Five questionnaire (owner) and the DPQ and C-BARQ tools (dog), it analyzes the links between psychological profiles and canine behavior. Results show that certain trait pairings increase relational satisfaction, while others lead to behavioral issues or breakdowns in the bond. Emotional synchronization and affective contagion are also explored to understand mutual adjustment within the dyad. By combining ethology, psychology, and behavioral data, this work proposes compatibility prediction tools and suggests practical criteria to guide adopters toward more sustainable and fulfilling human-dog relationships.Ce travail vise à identifier les combinaisons de traits de personnalité humain et de tempérament canin favorisant une relation harmonieuse, afin de limiter les échecs d’adoption. À partir des questionnaires Big Five (propriétaire), DPQ et C-BARQ (chien), il analyse les liens entre profil psychologique et comportement animal. Les résultats montrent que certaines associations de traits augmentent la satisfaction relationnelle, tandis que d’autres exposent à des troubles ou à une rupture du lien. La synchronisation émotionnelle et les effets de contagion affective sont également étudiés pour comprendre l’adaptation mutuelle au sein de la dyade. En croisant éthologie, psychologie et données comportementales, cette thèse propose des outils de prédiction de compatibilité et suggère des critères concrets pour mieux orienter les futurs adoptants
Cytotoxic CX3CR1+ Vδ1 T cells clonally expand in an interplay of CMV, microbiota, and HIV-1 persistence in people on antiretroviral therapy
No full textInternational audienceVδ 1 γδ T cells are key players in innate and adaptive immunity, particularly at mucosal interfaces such as the gut. An increase in circulating Vδ 1 cells has long been observed in people with HIV-1, but remains poorly understood. We performed a comprehensive characterization of Vδ 1 T cells in blood and duodenal intra-epithelial lymphocytes, obtained from endoscopic mucosal biopsies of 15 people with HIV-1 on antiretroviral therapy and 15 HIV-seronegative controls, in a substudy of the ANRS EP61 GALT study (NCT02906137). We deciphered the phenotype, functional profile, single-cell transcriptome and repertoire of Vδ 1 cells and unraveled their relationships with the possible triggers involved, in particular CMV and microbiota. We also assessed whether Vδ 1 T cells may play a role in controlling the HIV-1 reservoir. Vδ 1 T cells were mainly terminally differentiated effectors that clonally expanded in the blood with some trafficking with the gut of people with HIV-1. Most expressed CX3CR1 and displayed a highly cytotoxic profile, but low cytokine production, supported by a transcriptomic shift towards enhanced effector lymphocytes. This expansion was associated with CMV status and markers of occult replication, but also with changes in the duodenal and blood-translocated microbiota. Cytotoxic, but not IFN-γ-producing, Vδ 1 T cells were negatively associated with cell-associated HIV-1 RNA in both the blood and duodenal compartments. The increase in Vδ1 T cells observed in people with HIV-1 has multiple triggers, particularly CMV and microbiota, and may in turn contribute to the control of the HIV-1 reservoir
Le côté sombre de la résilience : révéler les dynamiques cachées du microbiote intestinal chez les chevaux – une solution agroécologique
No full textInternational audienceLe microbiote intestinal, une communauté complexe de micro-organismes dans le tractus digestif, joue un rôle crucial dans la santé et bien-être des animaux. Bien qu'il s'adapte rapidement aux changements environnementaux, les perturbations liées au stress peuvent entraîner des modifications de la composition du microbiote difficiles à inverser. L'axe intestin-cerveau est partie prenante dans cette dynamique. Nos recherches montrent que des chevaux logés individuellement dans des boxes, sans possibilité de pâturage ni socialisation en groupe, nourris avec des régimes hyperconcentrés, et soumis à un entraînement intensif et à la compétition, présentent un stress chronique significatif. Ce stress chronique est associé à une diversité et une composition microbienne intestinale altérées. De plus, le microbiote intestinal de ces animaux stressés démontre une résilience, signifiant que malgré des tentatives de modification, il revient à son état initial. Cette stabilité constitue un obstacle majeur à la récupération, empêchant une réorganisation vers un état microbien plus équilibré et favorable pour l’hôte. L’application des principes agroécologiques, en offrant aux chevaux la possibilité de pâturer librement et de socialiser sur de longues périodes, peut réduire le stress et favoriser un microbiote intestinal diversifié, contribuant ainsi à leur santé et à leur bien-être global
Outer Membrane Vesicles as a Versatile Platform for Vaccine Development: Engineering Strategies, Applications and Challenges
No full textInternational audienceOuter membrane vesicles (OMVs) are nanosized vesicles naturally secreted by Gram‐negative bacteria and represent a promising platform for vaccine development. OMVs possess inherent immunostimulatory properties due to the presence of pathogen‐associated molecular patterns (PAMPs), providing self‐adjuvanting capabilities and the ability to elicit both innate and adaptive immune responses. This review outlines the advantages of OMVs over traditional vaccine strategies, including their safety, modularity, and the potential for genetic engineering to enable targeted antigen delivery. We describe approaches to enhance OMVs yield and immunogenicity, such as modifications to reduce lipopolysaccharide (LPS) toxicity and systems enabling antigen localization—either on the surface or within the lumen—using fusion constructs like ClyA, Lpp‐OmpA, AIDA‐I, Hbp, and Sec/Tat signal peptides. We further summarize preclinical applications of OMVs‐based vaccines targeting bacterial pathogens, viral infections, and cancer. In addition, we address key challenges in large‐scale production, purification, and long‐term stability, and explore strategies for conjugating or encapsulating heterologous antigens. Overall, OMVs offer a versatile and scalable extracellular vesicle‐based platform with strong potential for next‐generation vaccines targeting diverse infectious diseases and beyond