The future challenge in animal production will be to provide food to a growing human population by respecting a balance between quality products, consumer acceptance and safety, as well as animal welfare. In a perspective of safe and sustainable food systems, reducing the use of antibiotics in livestock is a major concern. In fact, antibiotic resistance is one of the major medical challenges of the 21st century. The transfer of genes conferring resistance through the environment and the food chain, the potential for development of resistant bacteria and the appearance of therapeutic failures in human medicine, notably due to zoonotic bacteria, constitute major health issues for livestock farming sectors. In the pig breeding industry, the weaning period is often accompanied by a decreased growth rate caused by disparate food intake and diarrhoea due to digestive disorders that might be associated with bacterial population disequilibrium (i.e. dysbiosis) and/or opportunistic intestinal infections. Alarmingly, during this transition period the prophylactic use of antibiotics is still very frequent in order to limit piglet morbidity and mortality. Thus, reducing the prophylactic use of antibiotics in weaning pigs is a main issue and there is a strong need for alternatives. In this context, we have built a public-private partnership that gathers INRA scientists and industries from economic sectors of both animal feeding and pig breeding. PigletBiota is a precompetitive project that will study the physiological and genetic bases of the piglet sensitivity at weaning, as a prerequisite to identify innovative actions to adapt animals and pig production systems to a reduction of antibiotic use. The global aim of the PIGLETBIOTA project is to develop research that will contribute to adapt pig production systems to a reduction of antibiotics. The project proposes an integrative biology approach to determine the main factors influencing the variability of the individual’s robustness at weaning. We will monitor piglets for health, immune, stress and zootechnical traits and will characterize the intestinal microbiota diversity and composition as well as the contribution of host’s genotypes. The experimental design will combine various environments, including experimental and commercial farms, and ages at weaning and all animals will be fed without antibiotics. Animals (n~1000) will be clinically surveyed, measured for various traits related to production, immunity and stress, and genotyped with high-density SNP chips. The genetic parameters of the sensitivity at weaning will be estimated and genetic association studies performed. Faecal samples before and after the weaning date will be collected for characterizing the dynamics of the gut microbiota and studying its influence on the individual sensitivity at weaning. Animal and microbiota data will be vertically integrated in order to better understand the interplay between the these two levels of this biological system, and to develop robust indicators of weaning sensitivity. Finally, a functional screening using INRA platforms dedicated to human studies will be performed in order to detect active molecules to be tested in vivo and by using an axenic pigs model. The PigletBiota public-private consortium will favor translational research and innovation.

The worldwide emergence of antimicrobial resistant (AMR) bacteria relies on both the ability of mobile genetic elements (MGEs) to spread antibiotic resistance genes (ARGs), and the capacity of successful clones to disseminate. Evidence for the environmental origin of AMR in human and veterinary clinics highlights the mandate for the surveillance of emerging AMR. The objective of the PRE-EMPT project is to identify, and quantify the reservoir of mobile ARGs in different environments, and characterize the potential of these genes to be transferred to pathogens by combining high-throughput based techniques connecting the genes, the MGEs, and the bacterial communities. We will target three environmental sites, from urban, animal and littoral contexts, combine metagenomic techniques with enrichment methods (targeted PCR, hybridization capture, Hi-C), characterize the functional properties of the identified ARGs, and evaluate the dissemination of these ARGs in bacterial communities

Limiting the overall use of antibiotics constitutes a topical challenge for food animal industry. To reach this objective, vaccination plays a critical role by reducing the incidence and severity of high-impact diseases. At present, new alternatives to conventional antibody-based vaccines are necessary for controlling numerous animal diseases. In this context, CelBoVax proposes an innovative approach to produce next-generation vaccines aimed at boosting cattle cell-mediated immunity. As proof-of-concept, we will target Staphylococcus aureus, a major pathogen of dairy cows. By combining multidisciplinary approaches, our efforts will be focused on each step of a prototype vaccine production pipeline including: development and selection of new yeast-based antigen delivery systems, identification of pertinent candidate antigens by state-of-the-art proteomics and in silico analysis and setting up of simple and affordable assays to test the in vivo activity of candidate vaccines.

The ApiNewDrug project is looking for drug alternatives against zoonoses transmitted by two apicomplexan parasites, Toxoplasma and Cryptosporidium, responsible for toxoplasmosis and cryptosporidiosis respectively. These orally transmitted parasites have a significant impact on human and domestic animal health, their control can only be achieved through an integrated "One Health" action. Toxoplasmosis is a usually mild disease in immunocompetent humans that can turn into a major threat to the unborn and to immunocompromised people e.g. with acquired immunodeficiency syndrome (e.g. AIDS) or under chemo- and graft rejection therapies. In livestock, it can be the source of abortions leading to economic losses. Contamination occurs via ingestion of cysts (present in raw/undercooked meat) or oocysts contaminating plants or water. Cryptosporidiosis consists of acute gastrointestinal infections in immunocompromised people and young children, aggravated by malnutrition and leads to high morbidity in developing countries. Cryptosporidium also causes epidemics in industrialized countries due to high resistance to disinfectants other than ozone. Widespread in farms, C. parvum is also one of the two main causes of diarrhea in calves, inducing substantial economic losses to farmers and a source of contamination for humans. Despite the severity of the symptoms associated with these zoonoses, few treatments are available and their efficacy needs to be improved, especially in people with compromised immune systems. To enrich the therapeutic antiparasitic arsenal, an effort in the search for new compounds / target pairs is imperative. This knowledge will also provide a better understanding of the resistance mechanisms that might arise from the widespread use of drugs to treat human and veterinary clinical cases. Drug repositioning is the process of finding a new therapeutic indication for drugs approved by the health authorities (e.g. the Food and Drug Administration (FDA)) outside their original indication. It thus saves significant investments of time and money in the development of new drug candidates. This project capitalizes on solid preliminary results provided by the partners. We have screened a library of FDA-approved drug candidates and identified novel compounds that inhibit the growth of Toxoplasma and Cryptosporidium in the nanomolar range with excellent selectivity indexes. One molecule has already been identified as active against emblematic parasites of human (Plasmodium) and animal (Eimeria) infection, opening the way to the development of pan-apicomplexan treatments. In ApiNewDrug, we will explore the molecular targets of the best candidate molecules by chemogenomics and validate them by CRISPR/cas9-based editing of the parasite’s genome using the trackability of Toxoplasma and the recent advances in genetic manipulation for Cryptosporidium. We will then solve the crystallographic structure of molecules in complex with their target protein to investigate at an atomic-scale the modus operandi of the most promising compounds. The validation of the lead compounds will finally be carried out in vivo with animal models and targets of Toxoplasmosis and Cryptosporidiosis in order to produce a proof of concept for their future use in clinic.