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

Cell Microbiol. 2019 Jul;21(7):e13026. doi: 10.1111/cmi.13026. Epub 2019 May 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Infective Agents / pharmacology
  • Citrobacter rodentium / genetics*
  • Citrobacter rodentium / pathogenicity
  • DNA, Bacterial / genetics
  • DNA, Bacterial / isolation & purification
  • Enterobacteriaceae Infections / genetics*
  • Enterobacteriaceae Infections / microbiology
  • Enterobacteriaceae Infections / pathology
  • Enterohemorrhagic Escherichia coli / genetics
  • Enterohemorrhagic Escherichia coli / pathogenicity
  • Enteropathogenic Escherichia coli / genetics
  • Enteropathogenic Escherichia coli / pathogenicity
  • Gastrointestinal Microbiome / genetics*
  • Host-Pathogen Interactions / drug effects
  • Mice
  • NF-kappa B / genetics
  • Toll-Like Receptor 9 / genetics*

Substances

  • Anti-Bacterial Agents
  • Anti-Infective Agents
  • DNA, Bacterial
  • NF-kappa B
  • Toll-Like Receptor 9

Grant support