REDUCED INTESTINAL PRODUCTION OF CCL20 DURING CRYPTOSPORIDIOSIS IN NEONATAL MICE: A MECHANISM BY WHICH CRYPTOSPORIDIUM PARVUM ESCAPES ANTIMICROBIAL ACTIVITY OF CCL20 ?

Cryptosporidium parvum is an intestinal parasite that completes its life cycle in epithelial cells. This protozoan is frequently associated to diarrheal disease outbreaks and is now recognized as the second cause of diarrhoea in infants in Africa and Asia. In a neonatal mouse model, we previously showed that C. parvum infection of epithelial cells induces secretion of a broad range of chemokines allowing the recruitment of inflammatory cells to the site of infection. In this work, we observed that surprisingly, CCL20 production in the intestine of infected neonatal mice was significantly reduced by a mechanism independent of the enteric flora and IFNγ, a key cytokine for the resolution of this infection. MiR21 that functionally targets CCL20 is upregulated during the infection, and might participate to the downregulation of the chemokine. The tertiary structures of CCL20 and the anti-microbial peptide b-defensin are very similar, this confers to this chemokine a direct antimicrobial activity against Escherichia coli, Staphylococcus aureus and Candida albican. We observed that oral administration of recombinant CCL20 to neonatal mice reduced significantly intestinal parasite load by a mechanism independent of immune cell recruitment but rather by a direct cytolytic activity on free stages of the parasite as confirmed by in vitro experiments. Our findings demonstrate for the first time the direct antiparasitic activity of CCL20 against an enteric protozoan and its down-regulation during C. parvum infection, that might reflect a mechanism developed by the parasite to escape the protective innate immune response.