title: Invasive bacterial pathogens exploit TLR-mediated downregulation of tight junction components to facilitate translocation across the epithelium.
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.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Clarke
authors.forename: Nicholas
authors.initials: N
authors.lastname: Francella
authors.forename: Alyssa
authors.initials: A
authors.lastname: Huegel
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D057167:Claudins; D015536:Down-Regulation; D006193:Haemophilus influenzae / Q000276:immunology / Q000472:pathogenicity*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009297:Nasal Mucosa / Q000276:immunology* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000472:pathogenicity*; D019108:Tight Junctions / Q000276:immunology* / Q000382:microbiology; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D057167:Claudins; C507360:Cldn7 protein, mouse; D008565:Membrane Proteins; D051193:Toll-Like Receptors; C502009:claudin 10