Invasive bacterial pathogens exploit TLR-mediated downregulation of tight junction components to facilitate translocation across the epithelium

Cell Host Microbe. 2011 May 19;9(5):404-14. doi: 10.1016/j.chom.2011.04.012.

Abstract

Streptococcus pneumoniae and Haemophilus influenzae are members of the normal human nasal microbiota with the ability to cause invasive infections. Bacterial invasion requires translocation across the epithelium; however, mechanistic understanding of this process is limited. Examining the epithelial response to murine colonization by S. pneumoniae and H. influenzae, we observed the TLR-dependent downregulation of claudins 7 and 10, tight junction components key to the maintenance of epithelial barrier integrity. When modeled in vitro, claudin downregulation was preceded by upregulation of SNAIL1, a transcriptional repressor of tight junction components, and these phenomena required p38 MAPK and TGF-β signaling. Consequently, downregulation of SNAIL1 expression inhibited bacterial translocation across the epithelium. Furthermore, disruption of epithelial barrier integrity by claudin 7 inhibition in vitro or TLR stimulation in vivo promoted bacterial translocation. These data support a general mechanism for epithelial opening exploited by invasive pathogens to facilitate movement across the epithelium to initiate disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacterial Translocation*
  • Claudins
  • Down-Regulation
  • Haemophilus influenzae / immunology
  • Haemophilus influenzae / pathogenicity*
  • Membrane Proteins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Nasal Mucosa / immunology*
  • Nasal Mucosa / microbiology
  • Streptococcus pneumoniae / immunology
  • Streptococcus pneumoniae / pathogenicity*
  • Tight Junctions / immunology*
  • Tight Junctions / microbiology
  • Toll-Like Receptors / immunology*

Substances

  • Claudins
  • Cldn7 protein, mouse
  • Membrane Proteins
  • Toll-Like Receptors
  • claudin 10