Vibrio cholerae colonization of the arthropod intestine activates innate immune signaling in enteroendocrine cells via phosphorylation of the nuclear receptor ultraspiracle

The Gram-negative rod Vibrio cholerae causes profuse diarrhea in humans and is found in close association with both terrestrial and aquatic arthropods in the environment. We have previously shown that V. cholerae colonizes the arthropod intestine. Here we show that tryptophan produced by V. cholerae in the arthropod intestine is used by enterocytes to synthesize serotonin and signal to enteroendocrine cells (EECs) to activate the TNF-like immune deficiency pathway IMD. We define the EEC serotonin signaling pathway, which involves a subset of serotonin G protein-coupled receptors, Gq, phospholipase C, and protein kinase C. This pathway culminates in phosphorylation and potentiation of the nuclear receptor ultraspiracle, which binds the sex hormone ecdysone to activate IMD signaling. While IMD signaling increases antimicrobial peptide synthesis in all intestinal cell types, IMD signaling in EECs uniquely activates expression of the enteroendocrine peptide Tachykinin and the V. cholerae colonization factor Peritrophin-15a. We propose that, because V. cholerae secretes a metabolite that activates IMD signaling in EECs, it has evolved to exploit the arthropod intestinal innate immune response to maximize adhesion to the arthropod intestine.