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Role of p38 MAP kinase and transforming growth factor-beta signaling in transepithelial migration of invasive

Christoph Beisswenger1, Carolyn B Coyne2, Mikhail Shchepetov1

  • 1Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.

The Journal of Biological Chemistry
|July 26, 2007
PubMed

Insights

Streptococcus pneumoniae and Haemophilus influenzae disrupt airway epithelial barriers via Toll-like receptor 2 (TLR2) signaling. Inhibiting p38 MAPK or TGF-beta pathways blocks bacterial invasion, revealing common mechanisms for pathogen entry.

Area of Science:

  • Microbiology
  • Immunology
  • Cell Biology

Background:

  • Streptococcus pneumoniae and Haemophilus influenzae colonize the upper respiratory tract but can cause invasive disease.
  • Epithelial barrier integrity is crucial for preventing pathogen invasion.

Purpose of the Study:

  • To model and understand the mechanisms by which S. pneumoniae and H. influenzae breach the airway epithelial barrier.
  • To investigate the role of Toll-like receptor 2 (TLR2) signaling and downstream pathways in bacterial invasion.

Main Methods:

  • In vitro modeling using polarized respiratory epithelial cells.
  • Measurement of transepithelial electrical resistance (TER) to assess barrier function.
  • Analysis of p38 MAP kinase (MAPK) and transforming growth factor-beta (TGF-beta) signaling pathways.
  • In vivo studies using S. pneumoniae nasal infection models.

Main Results:

  • Bacterial migration across the epithelial barrier was preceded by a loss of TER.
  • Lipoteichoic acid from S. pneumoniae disrupted the epithelial barrier in a TLR2-dependent manner.
  • TLR2 ligand-induced barrier disruption correlated with p38 MAPK and TGF-beta signaling activation.
  • Inhibition of p38 MAPK or TGF-beta signaling effectively blocked bacterial migration in vitro and in vivo.

Conclusions:

  • Diverse bacteria, including S. pneumoniae and H. influenzae, utilize common signaling pathways (MAPK, TGF-beta) to disrupt epithelial barriers.
  • TLR2 signaling plays a critical role in mediating epithelial barrier disruption by S. pneumoniae.
  • Targeting these signaling pathways presents a potential strategy to inhibit bacterial invasion.

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