Aminopeptidase N-driven small intestinal epithelial transcytosis as a cornerstone of secretory IgA immunity upon oral vaccination

Protection against most enteropathogens requires intestinal secretory IgA responses. Key in this response is the proper uptake of antigens by the intestinal epithelium, which has evolved to restrict and regulate the uptake of macromolecules. Here we aim to explore if the selective targeting of antigens to aminopeptidase N (APN) present on small intestinal enterocytes activates these cells to release mediators which might promote secretory IgA responses. APN serves as a receptor for several enteropathogens, such as F4 fimbriated- enterotoxigenic E. coli and certain coronaviruses. We recently showed that APN-specific polyclonal antibodies and single domain antibodies are transported through the small intestinal epithelium upon binding to APN and elicit a potent antigen-specific intestinal immunity. This suggests that this targeting might serve as an antigen highway to the small intestinal immune system. This antigen transport through the epithelium is however on itself insufficient to trigger protective immunity. It also requires a shift from a tolerogenic to an immune-inductive microenvironment. This project will unravel if selective targeting to APN activates the release of mediators by small intestinal epithelial cells as well as if the identified molecules enhance intestinal secretory IgA responses in a large animal.