Porphyromonas gingivalis induces penetration of lipopolysaccharide and peptidoglycan through the gingival epithelium via degradation of junctional adhesion molecule 1

PLoS Pathog. 2019 Nov 7;15(11):e1008124. doi: 10.1371/journal.ppat.1008124. eCollection 2019 Nov.

Abstract

Porphyromonas gingivalis is a major pathogen in severe and chronic manifestations of periodontal disease, which is one of the most common infections of humans. A central feature of P. gingivalis pathogenicity is dysregulation of innate immunity at the gingival epithelial interface; however, the molecular basis underlying P. gingivalis-dependent abrogation of epithelial barrier function remains unknown. Gingival epithelial cells express junctional adhesion molecule (JAM1), a tight junction-associated protein, and JAM1 homodimers regulate epithelial barrier function. Here we show that Arg-specific or Lys-specific cysteine proteases (gingipains) secreted by P. gingivalis can specifically degrade JAM1 at K134 and R234 in gingival epithelial cells, resulting in permeability of the gingival epithelium to 40 kDa dextran, lipopolysaccharide (LPS), and proteoglycan (PGN). A P. gingivalis strain lacking gingipains was impaired in degradation of JAM1. Knockdown of JAM1 in monolayer cells and a three-dimensional multilayered tissue model also increased permeability to LPS, PGN, and gingipains. Inversely, overexpression of JAM1 in epithelial cells prevented penetration by these agents following P. gingivalis infection. Our findings strongly suggest that P. gingivalis gingipains disrupt barrier function of stratified squamous epithelium via degradation of JAM1, allowing bacterial virulence factors to penetrate into subepithelial tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteroidaceae Infections / immunology
  • Bacteroidaceae Infections / metabolism*
  • Bacteroidaceae Infections / microbiology
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cells, Cultured
  • Epithelium / metabolism*
  • Gingiva / metabolism*
  • Humans
  • Immunity, Innate
  • Lipopolysaccharides / metabolism*
  • Peptidoglycan / metabolism*
  • Porphyromonas gingivalis / physiology*
  • Proteolysis
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Tight Junctions
  • Virulence Factors

Substances

  • Cell Adhesion Molecules
  • F11R protein, human
  • Lipopolysaccharides
  • Peptidoglycan
  • Receptors, Cell Surface
  • Virulence Factors

Grants and funding

This research was supported by Grants-in-Aid for Young Scientists (B), Grant Numbers 15K20360 and 17K17083 (to HT), and Scientific Research (A), Grant Numbers 26253094 and 18H04068 (to AA), from the Japan Society for the Promotion of Science(https://www.jsps.go.jp/english/). The funders had no role in study design, data collection, decision to publish, or preparation of the manuscript.