TY  - JOUR
A1  - Däullary, Thomas
A1  - Imdahl, Fabian
A1  - Dietrich, Oliver
A1  - Hepp, Laura
A1  - Krammer, Tobias
A1  - Fey, Christina
A1  - Neuhaus, Winfried
A1  - Metzger, Marco
A1  - Vogel, Jörg
A1  - Westermann, Alexander J.
A1  - Saliba, Antoine-Emmanuel
A1  - Zdzieblo, Daniela
T1  - A primary cell-based in vitro model of the human small intestine reveals host olfactomedin 4 induction in response to Salmonella Typhimurium infection
JF  - Gut Microbes
N2  - Infection research largely relies on classical cell culture or mouse models. Despite having delivered invaluable insights into host-pathogen interactions, both have limitations in translating mechanistic principles to human pathologies. Alternatives can be derived from modern Tissue Engineering approaches, allowing the reconstruction of functional tissue models in vitro. Here, we combined a biological extracellular matrix with primary tissue-derived enteroids to establish an in vitro model of the human small intestinal epithelium exhibiting in vivo-like characteristics. Using the foodborne pathogen Salmonella enterica serovar Typhimurium, we demonstrated the applicability of our model to enteric infection research in the human context. Infection assays coupled to spatio-temporal readouts recapitulated the established key steps of epithelial infection by this pathogen in our model. Besides, we detected the upregulation of olfactomedin 4 in infected cells, a hitherto unrecognized aspect of the host response to Salmonella infection. Together, this primary human small intestinal tissue model fills the gap between simplistic cell culture and animal models of infection, and shall prove valuable in uncovering human-specific features of host-pathogen interplay.
KW  - intestinal enteroids
KW  - biological scaffold
KW  - Salmonella Typhimurium
KW  - OLFM4
KW  - NOTCH
KW  - filamentous Salmonella Typhimurium
KW  - bacterial migration
KW  - bacterial virulence
KW  - 3D tissue model
KW  - olfactomedin 4
KW  - infection
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350451
VL  - 15
IS  - 1
ER  - 
TY  - JOUR
A1  - Müller, Anna A.
A1  - Dolowschiak, Tamas
A1  - Sellin, Mikael E.
A1  - Felmy, Boas
A1  - Verbree, Carolin
A1  - Gadient, Sandra
A1  - Westermann, Alexander J.
A1  - Vogel, Jörg
A1  - LeibundGut-Landmann, Salome
A1  - Hardt, Wolf-Dietrich
T1  - An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection
JF  - PLoS Pathogens
N2  - Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and –injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf\(^{-/-}\) ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens.
KW  - NK cells
KW  - Salmonella Typhimurium
KW  - mucosal inflammation
KW  - diarrhea
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167429
VL  - 12
IS  - 6
ER  -