CD9 co-operation with syndecan-1 is required for a major staphylococcal adhesion pathway

Abstract

Objectives: Epithelial colonisation is a critical first step in bacterial pathogenesis. Staphylococcus aureus can utilise several host factors to associate with cells, including α5β1 integrin and heparan sulphate proteoglycans, such as the syndecans. Here, we demonstrate that a partner protein of both integrins and syndecans, the host membrane adapter protein tetraspanin CD9, is essential for syndecan-mediated staphylococcal adhesion. Fibronectin is also essential in this process while integrins are only critical for post-adhesion entry into human epithelial cells. Methods and Results: Treatment of epithelial cells with CD9-derived peptide or heparin caused significant reductions in staphylococcal adherence, dependent on both CD9 and syndecan-1. Exogenous fibronectin caused a CD9-dependent increase in staphylococcal adhesion whereas blockade of β1 integrins did not affect adhesion but did reduce the subsequent internalisation of adhered bacteria. CD9 disruption or deletion increased β1 integrin-mediated internalisation, suggesting that CD9 coordinates sequential staphylococcal adhesion and internalisation. Conclusions: CD9 controls staphylococcal adhesion through syndecan-1, using a mechanism that likely requires CD9-mediated syndecan organisation to correctly display fibronectin at the host cell surface. We propose that CD9-derived peptides or heparin analogues could be developed as anti-adhesion treatments to inhibit the initial stages of staphylococcal pathogenesis.

Global impact of proteoglycan science on human diseases

“…Through utilization of the diverse and complex signaling pathways outlined previously, syndecans and its HS chains affect the homeostasis of various organs and the pathogenesis of several neoplastic diseases including those of the liver, 77 colon, 78 breast, 79 plasma cells, 74 , 75 , 80 and in bacterial infection. 81 , 82 Syndecans are directly involved in inflammation (see the following text) and are often upregulated in inflammatory diseases concurrent with enhancement of cytokine and chemokine levels. This dual activation boosts leukocyte adhesion to endothelial cells which is fortified by integrin-controlled signaling and other cell adhesion molecules, leading to the arrest of leukocyte rolling.…”