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.