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Research unit
FSVO
Project number
1.20.01
Project title
Harnessing trained immunity to enhance resistance of piglets against infections

Texts for this project

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Key words
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Short description
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Project aims
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Publications / Results
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CategoryText
Key words
(German)

Trainierte Immunität, Immunostimulation, Antibiotika Resistenz, absetzbedingte Infektionen, Absetzdurchfall, Ferkel, E. coli

Key words
(English)

Trained immunity, immunostimulation, antibiotic resistance, postweaning infections, postweaning diarrhea, piglets, E. coli

Key words
(French)

Immunité entrainée, immunostimulation, résistance aux antibiotiques, infections de post sevrage, diarrhée post-sevrage, porcelets, E. coli

Short description
(English)

There is an urgent need for alternatives to antibiotics to ensure animal health and consumer safety. Post weaning diarrhea (PWD), a multifactorial disease caused most frequently by Escherichia coli (E.coli), is a major health issue in pig production worldwide requiring massive antibiotics. The project will tackle this problem by applying the concept of “trained immunity”, based on the observation that the innate immune system can be primed, to acquire a higher resistance against unrelated infections 1. The applicants have made significant progress in understanding in detail the response of the porcine innate immune system to stimulation 2, 3, 4, 5, 6. Furthermore, a methodology was established to dissect innate immune responses in vivo using “system immunology” techniques 7, 8. Thus, we will translate this new knowledge and the novel technologies for the development of new intervention options for PWD. This will be achieved in a synergistic partnership covering the required immunological expertise, knowhow on adjuvant formulation and on E. coli.

Short description
(French)

La recherche d’alternative aux antibiotiques est devenue cruciale pour assurer la santé animale et la protection du consommateur. La diarrhée de post sevrage (DPS), maladie polyfactorielle souvent causée par E.coli, est un problème majeur pour l’élevage de porc générant l’utilisation massive d’antibiotiques. Le projet exploite le concept d’immunité entrainée, selon lequel l’immunité innée activée par une infection microbienne procure une meilleure protection contre d’autres infections ultérieures  1. Les candidats possèdent une connaissance approfondie du mécanisme de stimulation et de réponse du système immunitaire inné du porc 2, 3, 4, 5, 6. La nouvelle technologie du « système immunologie » est utilisée pour comprendre la réponse immunitaire inné in vivo 7, 8. Ces nouvelles connaissances et technologies permettent de proposer de nouvelles solutions pour les DPS. Le présent partenariat constitue une parfaire synergie entre l’expertise en immunologie, le savoir-faire en formulation et les connaissance du modèle E.coli.

Project aims
(English)

The overall aims of this project are to translate recent immunological and technical advances to the development of new prophylactic and metaphylactic treatment options for multifactorial infectious diseases in piglets. To reach this goal we will focus on E. coli diarrhea as an important and relevant model. The immunological and technical advances which are the basis of this project are:

1.      The fact that also the innate immune system has a kind of memory and can be “trained”. This is based epidemiological data in humans indicating that mild infections or vaccinations, such as with bacilli Calmette-Guerin (BCG), have protective effects against completely heterologous infections, reducing overall mortality for up to one year 30, 31. There is now plenty of experimental evidence that the innate immune system can be primed upon encounter with certain pathogens, pathogen-associated molecular patterns (PAMPs) or host cell-derived damage-associated molecular patterns (DAMP), to acquire a higher resistance against unrelated pathogen infection 32, 33, 34. This “trained immunity” has been shown to be based on immunological, metabolic and epigenetic re-programming of cells from the innate immune system causing for instance is a shift from oxidative phosphorylation to aerobic glycolysis mediated by the Akt/mTOR/HIF-1a pathway 1, 35, 36, 37, 38. The glycolysis, glutaminolysis, and cholesterol synthesis pathways in monocytes and macrophages were identified as the essential underlying mechanism linking epigenetic rewiring and the induction of improved innate immunity 39, 40. Examples for epigenetic changes are histone H3K4 trimethylation and H3K27 acetylation, both associated with active chromatin, and H3K9 trimethylation, a repressive marker 35, 39, 41. As a result, innate immune cells such as monocytes and macrophages produce more proinflammatory cytokines such as TNF, IL-6 and IL-1 b 33, 41, 42, 43. Currently available reports indicate a duration of trained immunity effects for up to 3 months, but long-lasting effects are likely with respect to the effect of training on adaptive immune responses 41. Importantly trained immunity also impacts hematopoiesis of myeloid cells in a long-lasting manner, giving rise to epigenetically modified monocytes 44 and macrophages 45, 46.

2.      We have identified and characterized the main porcine antigen presenting cells such as monocytic cells and dendritic cells, as well as potent immunostimulants targeting these important initiators of immune responses 3, 4, 6.

3.      We have identified potent delivery systems for immunostimulatory ligands to induce innate immune responses in vivo in pigs the most effective being particular oil-in-water formulations or cationic liposomal nanoparticles 8.

4.      We have established a bioinformatics pipeline using transcriptomic data from peripheral blood cells which was proven to provide very sensitive and meaningful readouts to measure innate immune responses in vivo using peripheral blood of pigs and sheep. This has enabled to identify potent formulations of ligands inducing innate immune responses and how such responses correlate to adaptive and inflammatory responses 7, 8.  

 

Based on the above, the specific tasks of the project will be:

Task 1. Identify in vitro the most potent ligands able to induce features associated with “trained immunity”.

Task 2. Design optimized oil-in-water or nanoparticle-based delivery system for the selected ligands to be most potent immunostimulants, and test in vivo ability to induce trained immunity.

Task 3. Evaluate the protective value of the immunostimulant (formulated ligand) in an E. coli PWD challenge model.

Publications / Results
(German)
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URL-addresses
(German)