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Infection, innate immune signaling and cancer in the gut - human organdies as disease model

In the gastrointestinal tract, the epithelial lining acts as physical and immunological barrier between the microorganisms of the gut and the body. The epithelial cells can sense microorganisms, which activates innate immune signaling pathways and leads to an inflammatory response. Chronic inflammations, for example caused by infection with the gastric pathogen Helicobacter pylori, can cause serious disease, including cancer.

We analyse the molecular basis of innate immune signaling in the epithelium of the gastrointestinal tract and the host cell response to infections such as with H. pylori or Epstein Barr Virus. To these ends, we use adult stem cell-derived organoids.

We generated a biobank of human and murine organoids covering 6 sites from stomach to colon. RNA-sequencing showed that the tissue identity is conserved in the adult stem cells. Moreover, components of the epithelial innate immune sensing, such as toll like receptors, are part of the tissue identity and highly organized along the gastrointestinal tract. This organization is for a large part determined by developmental processes rather than by environmental factors.

Infection of the organoids with pathogens demonstrates that normal gastric organoids can be well infected with H. pylori and single cell RNA sequencing of infected cells reveals a preferential target cell of H. pylori. EBV on the other hand does not infect healthy gastric organoids, but only gastric cancer organoids, indicating that in the case of EBV, cellular changes have to occur to enable infection.