Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence.
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.
Park
P W
PW
Division of Newborn Medicine, Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. pwpark@bcm.tmc.edu
Pier
G B
GB
Hinkes
M T
MT
Bernfield
M
M
D000818:Animals; D000831:Animals, Newborn; D001422:Bacterial Adhesion; D004195:Disease Models, Animal; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008171:Lung Diseases / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry / Q000502:physiology*; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000472:pathogenicity*; D053668:Syndecan-1; D053667:Syndecans; D014774:Virulence
D006493:Heparin; D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D053668:Syndecan-1; D053667:Syndecans; C508242:Sdc1 protein, mouse