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B3 GGiardia duodenalis – natural human tissue interaction and outcome for intestinal barrier function (Aebischer)

Research Group: Robert Koch-Institute, Division 16 Mycotic and Parasitic Agents and Mycobacteria
& Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin
Address: FG16, Robert Koch-Institute, Nordufer 20, 13353 Berlin

Dr. Toni Aebischer

Doctoral Researcher: David Holthaus, Sharareh Salehi

Project Description

State of the art:
Giardia duodenalis (Gd) designates a species complex of protozoan parasites causing acute
and chronic intestinal disease. Pathogenesis and mechanisms leading to immune responses
to this infection remain poorly understood and co-infection, e.g., with ascarids is frequent but its
effect unknown. Release of Gd-factors, e.g. enzymes of the arginine (Arg)-dehydrolase (ADH-)
pathway, may induce acute Arg depletion with influence onresponses of dendritic cells (DC),
a cell type linked to in vivo outcome. The mutual influence of epithelial cells (EC) / DC, viable
parasites, factors related to microbiota, coinfecting pathogens such as helminths or host
determinants, as shown for cystic fibrosis (CF), on barrier function appears likely but has yet to
be determined.

Previous own work:
J.-D. Schulzke’s group (Co-PI of 1st PhD fellow project) has shown EC
dysfunction in patients with chronic Gd infection. We showed that Gd Arg-depletion
modulates DC response and identified ascarids as a main co-infecting pathogen in
giardiasis. RTG2046 1st generation student, Martin Kraft, demonstrated that Gd alone did
not affect barrier function of CaCo-2 cell line-derived epithelial models. He adapted human
intestinal organoids to study parasite – host tissue interactions under conditions closer to real
infection, since organoids display several different cell populations of gut epithelia, and he was
able to establish cultures of different genetic make-up, in particular, of ‘normal’ donors and CF

Hypotheses and work plan:
1) Microbial priming and/or molecules released by co-infecting Ascaris spp. cause pathogenic
alteration of human epithelia’s response to Gd depending or not on presence of human DC.
2) CF-related functional differences in epithelia impact the effect of Gd colonization, alone or
in combination with aforementioned microbial or helminth-derived factors.
The experimental approach to test these hypotheses will exploit the organoid culture and -
derived transwell compartmentalized 2D system established for infection experiments during
the 1st funding period. This is thought to be the best primary tissue model for studying humanpathogenic
Gd that will be conditioned using human-derived bacteria to engineer a proxy
of the natural situation. Ascaris excretory/secretory factors will be studied in collaboration with
A1/B4 to investigate effects of co-infection. Human DC will be generated as before. Read
outs on barrier and epithelial function will be based on the ability to measure trans-epithelial
electrical resistance, to perform dual transcriptomic profiling of host and parasite
responses and advanced microscopic analyses.

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