TLR9 limits enteric antimicrobial responses and promotes microbiota-based colonisation resistance during Citrobacter rodentium infection.

Mammalian cells express an array of toll-like receptors to detect and respond to microbial pathogens, including enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC). These clinically important attaching and effacing (A/E) pathogens infect the apical surface of intestinal epithelial cells, causing inflammation as well as severe diarrheal disease. Because EPEC and EHEC are human-specific, the related murine pathogen Citrobacter rodentium has been widely used to define how hosts defend against A/E pathogens. This study explored the role of TLR9, a receptor that recognises unmethylated CpG dinucleotides present in bacterial DNA, in promoting host defence against C. rodentium. Infected Tlr9 mice suffered exaggerated intestinal damage and carried significantly higher (10-100 fold) pathogen burdens in their intestinal tissues as compared with wild type (WT) mice. C. rodentium infection also induced increased antimicrobial responses, as well as hyperactivation of NF-κB signalling in the intestines of Tlr9 mice. These changes were associated with accelerated depletion of the intestinal microbiota in Tlr9 mice as compared with WT mice. Notably, antibiotic-based depletion of the gut microbiota in WT mice prior to infection increased their susceptibility to the levels seen in Tlr9 mice. Our results therefore indicate that TLR9 signalling suppresses intestinal antimicrobial responses, thereby promoting microbiota-mediated colonisation resistance against C. rodentium infection.