2-O-Sulfated Domains in Syndecan-1 Heparan Sulfate Inhibit Neutrophil Cathelicidin and Promote Staphylococcus aureus Corneal Infection.

Abstract

Ablation of syndecan-1 in mice is a gain of function mutation that enables mice to significantly resist infection by several bacterial pathogens. Syndecan-1 shedding is induced by bacterial virulence factors, and inhibition of shedding attenuates bacterial virulence, whereas administration of purified syndecan-1 ectodomain enhances virulence, suggesting that bacteria subvert syndecan-1 ectodomains released by shedding for their pathogenesis. However, the pro-pathogenic functions of syndecan-1 ectodomain have yet to be clearly defined. Here, we examined how syndecan-1 ectodomain enhances Staphylococcus aureus virulence in injured mouse corneas. We found that syndecan-1 ectodomain promotes S. aureus corneal infection in an HS-dependent manner. Surprisingly, we found that this pro-pathogenic activity is dependent on 2-O-sulfated domains in HS, indicating that the effects of syndecan-1 ectodomain are structure-based. Our results also showed that purified syndecan-1 ectodomain and heparan compounds containing 2-O-sulfate motifs inhibit S. aureus killing by antimicrobial factors secreted by degranulated neutrophils, but does not affect intracellular phagocytic killing by neutrophils. Immunodepletion of antimicrobial factors with staphylocidal activities demonstrated that CRAMP, a cationic antimicrobial peptide, is primarily responsible for S. aureus killing among other factors secreted by degranulated neutrophils. Furthermore, we found that purified syndecan-1 ectodomain and heparan compounds containing 2-O-sulfate units potently and specifically inhibit S. aureus killing by synthetic CRAMP. These results provide compelling evidence that a specific subclass of sulfate groups, and not the overall charge of HS, permits syndecan-1 ectodomains to promote S. aureus corneal infection by inhibiting a key arm of neutrophil host defense.

• Authors: Atsuko Hayashida, Shiro Amano, Richard L Gallo, Robert J Linhardt, Jian Liu, Pyong Woo Park
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 26 Pg. 16157-67 (Jun 26 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 25931123 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antimicrobial Cationic Peptides
• Cathelicidins
• Syndecan-1

Topics

• Animals
• Antimicrobial Cationic Peptides
• Cathelicidins (immunology)
• Corneal Diseases (genetics, immunology, microbiology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neutrophils (immunology, microbiology)
• Protein Structure, Tertiary
• Staphylococcal Infections (genetics, immunology, microbiology)
• Staphylococcus aureus (immunology, pathogenicity, physiology)
• Syndecan-1 (chemistry, genetics, metabolism)
• Virulence