Vibrio cholerae Arrests Intestinal Epithelial Proliferation through T6SS-dependent Activation of the Bone Morphogenetic Protein Pathway.

Abstract

To maintain an effective barrier, intestinal epithelial progenitor cells must divide at a rate that matches the loss of dead and dying cells. Otherwise, epithelial breaches expose the host to systemic infection by gut-resident microbes. Unlike most pathogens, Vibrio cholerae blocks tissue repair by arresting progenitor proliferation in the Drosophila infection model. At present, we do not understand how Vibrio circumvents such a critical antibacterial defense. In a series of genetic experiments, we found that V. cholerae blocks epithelial repair by activating the growth inhibitor Bone Morphogenetic Protein (BMP) pathway in progenitors. Specifically, we discovered that interactions between Vibrio and gut commensals initiate BMP signaling via host innate immune defenses. Notably, we found that Vibrio also activates BMP and arrests proliferation in zebrafish intestines, indicating an evolutionarily conserved link between infection, BMP and failure in tissue repair. Combined, our study highlights how enteric pathogens engage host immune and growth regulatory pathways to disrupt intestinal epithelial repair.