Shigella infection is facilitated by interaction of human enteric α-defensin 5 with colonic epithelial receptor P2Y11.

Human enteric α-defensin 5 (HD5) is an immune system peptide that acts as an important antimicrobial factor but is also known to promote pathogen infections by enhancing adhesion of the pathogens. The mechanistic basis of these conflicting functions is unknown. Here we show that HD5 induces abundant filopodial extensions in epithelial cells that capture Shigella, a major human enteroinvasive pathogen that is able to exploit these filopodia for invasion, revealing a mechanism for HD5-augmented bacterial invasion. Using multi-omics screening and in vitro, organoid, dynamic gut-on-chip and in vivo models, we identify the HD5 receptor as P2Y11, a purinergic receptor distributed apically on the luminal surface of the human colonic epithelium. Inhibitor screening identified cAMP-PKA signalling as the main pathway mediating the cytoskeleton-regulating activity of HD5. In illuminating this mechanism of Shigella invasion, our findings raise the possibility of alternative intervention strategies against HD5-augmented infections.