Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence

Nature. 2001 May 3;411(6833):98-102. doi: 10.1038/35075100.

Abstract

Cell-surface heparan sulphate proteoglycans (HSPGs) are ubiquitous and abundant receptors/co-receptors of extracellular ligands, including many microbes. Their role in microbial infections is poorly defined, however, because no cell-surface HSPG has been clearly connected to the pathogenesis of a particular microbe. We have previously shown that Pseudomonas aeruginosa, through its virulence factor LasA, enhances the in vitro shedding of syndecan-1-the predominant cell-surface HSPG of epithelia. Here we show that shedding of syndecan-1 is also activated by P. aeruginosa in vivo, and that the resulting syndecan-1 ectodomains enhance bacterial virulence in newborn mice. Newborn mice deficient in syndecan-1 resist P. aeruginosa lung infection but become susceptible when given purified syndecan-1 ectodomains or heparin, but not when given ectodomain core protein, indicating that the ectodomain's heparan sulphate chains are the effectors. In wild-type newborn mice, inhibition of syndecan-1 shedding or inactivation of the shed ectodomain's heparan sulphate chains prevents lung infection. Our findings uncover a pathogenetic mechanism in which a host response to tissue injury-syndecan-1 shedding-is exploited to enhance microbial virulence apparently by modulating host defences.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Bacterial Adhesion
  • Disease Models, Animal
  • Heparin / pharmacology
  • Heparitin Sulfate / metabolism
  • Lung / metabolism
  • Lung / microbiology
  • Lung Diseases / metabolism
  • Lung Diseases / microbiology
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Protein Structure, Tertiary
  • Proteoglycans / chemistry
  • Proteoglycans / physiology*
  • Pseudomonas Infections / immunology
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / metabolism
  • Pseudomonas aeruginosa / pathogenicity*
  • Syndecan-1
  • Syndecans
  • Virulence

Substances

  • Membrane Glycoproteins
  • Proteoglycans
  • Sdc1 protein, mouse
  • Syndecan-1
  • Syndecans
  • Heparin
  • Heparitin Sulfate