A primary cell-based in vitro model of the human small intestine reveals host olfactomedin 4 induction in response to Salmonella Typhimurium infection

ABSTRACT

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.

KEYWORDS:

• Intestinal enteroids
• biological scaffold
• Salmonella Typhimurium
• OLFM4
• NOTCH
• filamentous Salmonella Typhimurium
• bacterial migration
• bacterial virulence
• 3D tissue model
• olfactomedin 4
• infection

Acknowledgments

We thank S. Reichardt, M. Krafft, and E. Reitenbach for their excellent technical support and assistance; C. Stigloher, C. Gehrig-Höhn, and D. Bunsen for the excellent support during SEM and TEM preparation and imaging; M. Heckmann and C. Werner for kindly provision of IMARIS. A. Gerhartl and A. Brachner for their support in high-throughput qPCR barrier chip measurement; Sara Giddins for editorial support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Repository: https://www.ncbi.nlm.nih.gov/geo/ Accession number: GSE217976

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2186109

Additional information

Funding

 The work was supported by the Deutsche Forschungsgemeinschaft (DFG) [270563345]. in the context of the GRK 2157. Furthermore, the DFG funded the SEM (JEOL JSM-7500F) [218894895] and the TEM (JEOL JEM 2100) [218894163]. T.D, A.-E.S., and O.D. thanks DFG for funding through GRK2157. A.-E.S. thanks DFG funding SFB1583 (DECIDE; Project B05). A.-E.S. thank the Single Cell Center Würzburg for support. T.K. thanks DFG funding via SFB1525 (Cardio-Immuno Interface: PS2 Project).