title: Role of p38 MAP kinase and transforming growth factor-beta signaling in transepithelial migration of invasive bacterial pathogens.
abstract: Streptococcus pneumoniae and Haemophilus influenzae are human pathogens that often asymptomatically colonize the mucosal surface of the upper respiratory tract, but also occasionally cause invasive disease. The ability of these species to traverse the epithelium of the airway mucosa was modeled in vitro using polarized respiratory epithelial cells in culture. Migration across the epithelial barrier was preceded by loss of transepithelial resistance. Membrane products of S. pneumoniae that included lipoteichoic acid induced disruption of the epithelial barrier in a Toll-like receptor 2-dependent manner. This result correlates with a recent genetic study that associates increased TLR2 signaling with increased rates of invasive pneumococcal disease in humans. Loss of transepithelial resistance by the TLR2 ligand correlated with activation of p38 MAP kinase and transforming growth factor (TGF)-beta signaling. Activation of p38 MAPK and TGF-beta signaling in epithelial cells upon nasal infection with S. pneumoniae was also demonstrated in vivo. Inhibition of either p38 MAPK or TGF-beta signaling was sufficient to inhibit the migration of S. pneumoniae or H. influenzae. Our data shows that diverse bacteria utilize common mechanisms, including MAPK and TGF-beta signaling pathways to disrupt epithelial barriers and promote invasion.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Christoph
authors.initials: C
authors.lastname: Beisswenger
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Coyne
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Shchepetov
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104. Electronic address: weiser@mail.med.upenn.edu.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D006192:Haemophilus Infections / Q000276:immunology* / Q000473:pathology; D006193:Haemophilus influenzae / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008954:Models, Biological; D011008:Pneumococcal Infections / Q000276:immunology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000276:immunology* / Q000472:pathogenicity; D013682:Teichoic Acids / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; C495342:TLR2 protein, human; D013682:Teichoic Acids; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta; C009900:lipoteichoic acid; D048051:p38 Mitogen-Activated Protein Kinases