Role of p38 MAP Kinase and Transforming Growth Factor-β 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)-␤ signaling. Activation of p38 MAPK and TGF-␤ signaling in epithelial cells upon nasal infection with S. pneumoniae was also demonstrated in vivo. Inhibition of either p38 MAPK or TGF-␤ 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-␤ signaling pathways to disrupt epithelial barriers and promote invasion.

Inhibition of basal p38 or JNK activity enhances epithelial barrier function through differential modulation of claudin expression

“…Thus, inhibition of p38 was reported to prevent the disruption of TJ barrier induced by various stimuli in different epithelial cell types (8,43,(55)(56)(57). To our knowledge, a role for JNK in the control of TJ function has been previously documented in a single study (30) showing that inhibition of JNK signaling reduces claudin-2 expression in MDCK II cells.…”

Early Bacterial Colonization Induces Toll-Like Receptor-Dependent Transforming Growth Factor β Signaling in the Epithelium

“…Animal tissues were obtained after decapitation, fixed, and decalcified by serial overnight incubations in 4% paraformaldehyde-PBS-Decal decalcification agent (Decal Corporation). Tissue was embedded in paraffin, and immunohistochemistry was performed as described earlier (2). p-p38 MAPK (Cell Signaling), ATF-2 (Cell Signaling), and p-Smad2 and -3 (Abcam) were detected with primary antibodies diluted 1:100 in PBT (1ϫ PBS, 0.1% bovine serum albumin, 0.2% Triton X-100).…”

“…These events could be required for the trafficking of immune cells and inflammatory mediators such as neutrophils and complement to the airway lumen, where microbes reside. Opening of the barrier, however, may also result in invasion by bacteria that are not adequately controlled by these host responses (2).…”

“…Transforming growth factor ␤ (TGF-␤) signaling through the TGF-␤ receptor is involved in the remodeling and repair of epithelial surfaces but also mediates epithelial-to-mesenchymal transition, thereby contributing to the progression of complex diseases such as pulmonary fibrosis and cancer (28,29,44). Moreover, H. influenzae and S. pneumoniae have been shown to stimulate TGF-␤ signaling in respiratory cells in vitro (2,29). We have demonstrated that stimulation of TGF-␤ signaling in polarized respiratory epithelial cells in culture results in the opening of tight junctions and loss of barrier integrity.…”

Innate Immunity of Airway Epithelium and COPD

“…TLR5 recgonizes flagella of P. aeruginosa and Burkholderia cenocepacia and activate NF-κB (Adamo et al, 2004;Urban et al, 2004;Zhang et al, 2005). Haemophilus infIuenzae traverses polarized airway epithelial cells by interacting with TLR2, which then activates p38 mitogen activated protein (MAP) kinase and TGF-Signalling (Beisswenger et al, 2007). TLR3 recognizes double stranded (ds)-RNA, an intermediate generated during RNA virus replication and elicits chemokine and type I IFN responses by MyD88-independent signaling mechanism (Gern et al, 2003;Wang et al, 2009).…”