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Spatio-temporal regulation of viral-induced innate immune response in intestinal epithelial cells

Final Report Summary - IIIECS (Spatio-temporal regulation of viral-induced innate immune response in intestinal epithelial cells)

Final report project IIIECs
Human intestinal epithelial cells (IECs) lining the surface of our gastrointestinal tract represent the primary barrier separating us from the outside environment.
The cells have developed mechanisms to tolerate the presence of the commensal microbiota residing in the lumen of our gut but in the same time they remain full responsive to enteric pathogen challenges. Dysregulation of this finely tune balance can results in the development of chronic inflammation that can ultimately progress and lead to inflammatory bowel diseases. The aims of this Marie Curie Career re-integration grant was to identified the molecular mechanism by which such equilibrium can be achieved at the intestinal mucosa.
We found that the polarized nature of the intestinal epithelial cells is key to mediate gut homeostasis. These cells have their apical sides in constant contact with the lumenal commensal flora and their basolateral side facing the sterile lamina propria. Using human primary non-transformed IECs by using mini-gut organoids, we found that IECs mount a distinct immune response as a function of infection side (apical vs basolateral). We identified the mechanisms that lead to this assymetric response and identify novel functions of cytokines to regulate immune response in the human gut. In brief, we have identified novel mechanisms developed by hIECs to regulate their immune response. This polarized response would represent a strategy to maintain gut immune homeostasis by avoiding excessive response against microbes incl. viruses located in the lumenal side while maintaining full responsiveness against invasive pathogens that have passed the epithelium barrier.
In parallel to these findings, by using the mammalian reovirus as a model enteric virus, we identified novel strategies develop by this virus to efficiency infect the gastrointestinal tract.