Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence

Cell-surface heparan sulphate proteoglycans (HSPGs) are ubiquitous and abun dant receptors/co-receptors of extracellular ligands(1,2), including many m icrobes(3-10). Their role in microbial infections is poorly defined, howeve r, because no cell-surface HSPG has been clearly connected to the pathogene sis of a particular microbe. We have previously shown that Pseudomonas aeru ginosa, through its virulence factor LasA, enhances the in vitro shedding o f syndecan-1-the predominant cell-surface HSPG of epithelia(11). Here we sh ow that shedding of syndecan-1 is also activated by P. aeruginosa in vivo, and that the resulting syndecan-1 ectodomains enhance bacterial virulence i n newborn mice. Newborn mice deficient in syndecan-1 resist P. aeruginosa l ung infection but become susceptible when given purified syndecan-1 ectodom ains or heparin, but not when given ectodomain core protein, indicating tha t 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.