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Published on: June 30, 2016
Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence
P W Park1, G B Pier, M T Hinkes
1Division of Newborn Medicine, Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. pwpark@bcm.tmc.edu
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.
Insights
Pseudomonas aeruginosa infection is enhanced by shed syndecan-1 ectodomains, which contain heparan sulfate chains. Inhibiting shedding or heparan sulfate prevents P. aeruginosa lung infection in mice.
Area of Science:
- Microbiology
- Cell Biology
- Infectious Diseases
Background:
- Cell-surface heparan sulphate proteoglycans (HSPGs) are key receptors for extracellular ligands, including microbes.
- The role of HSPGs in microbial pathogenesis remains largely undefined.
- Pseudomonas aeruginosa virulence factor LasA was previously shown to enhance syndecan-1 shedding in vitro.
Purpose of the Study:
- To investigate the in vivo role of syndecan-1 shedding in Pseudomonas aeruginosa infection.
- To determine if shed syndecan-1 ectodomains contribute to bacterial virulence.
- To elucidate the specific components of shed syndecan-1 responsible for enhancing virulence.
Main Methods:
- In vivo studies using newborn mice models with and without syndecan-1.
- Administration of purified syndecan-1 ectodomains and heparin to assess their effect on infection.
- Inhibition of syndecan-1 shedding and inactivation of heparan sulphate chains.
- Infection assays with Pseudomonas aeruginosa.
Main Results:
- Syndecan-1 shedding is activated by P. aeruginosa in vivo.
- Shed syndecan-1 ectodomains significantly enhance P. aeruginosa virulence in newborn mice.
- Heparan sulphate chains on the ectodomain, not the core protein, are responsible for enhancing virulence.
- Newborn mice deficient in syndecan-1 are resistant to P. aeruginosa lung infection.
- Inhibition of shedding or heparan sulphate function prevents infection.
Conclusions:
- A novel pathogenic mechanism where Pseudomonas aeruginosa exploits host syndecan-1 shedding to enhance virulence.
- Heparan sulphate chains on shed syndecan-1 ectodomains act as crucial effectors in P. aeruginosa pathogenesis.
- Targeting syndecan-1 shedding or its heparan sulphate chains represents a potential therapeutic strategy against P. aeruginosa infections.
