Syndecan-1 Promotes Streptococcus pneumoniae Corneal Infection by Facilitating the Assembly of Adhesive Fibronectin Fibrils.

Subversion of heparan sulfate proteoglycans (HSPGs) is thought to be a common virulence mechanism shared by many microbial pathogens. The prevailing assumption is that pathogens co-opt HSPGs as cell surface attachment receptors or as inhibitors of innate host defense. However, there are few data that clearly support this idea We found that deletion of syndecan-1 (Sdc1), a major cell surface HSPG of epithelial cells, causes a gain of function in a mouse model of scarified corneal infection, where corneas were significantly less susceptible to infection. Administration of excess Sdc1 ectodomains significantly inhibited corneal infection, suggesting that Sdc1 promotes infection as a cell surface attachment receptor. However, did not interact with Sdc1 and Sdc1 was shed upon infection, indicating that Sdc1 does not directly support adhesion. Instead, Sdc1 promoted adhesion by driving the assembly of fibronectin (FN) fibrils in the corneal basement membrane to which attaches when infecting injured corneas. specifically bound to corneal FN via PavA, and PavA deletion significantly attenuated virulence in the cornea. Excess Sdc1 ectodomains inhibited corneal infection by binding to the Hep II domain and interfering with PavA binding to FN. These findings reveal a previously unknown virulence mechanism of where key extracellular matrix (ECM) interactions and structures that are essential for host cell homeostasis are exploited for bacterial pathogenesis. Bacterial pathogens have evolved several ingenious mechanisms to subvert host cell biology for their pathogenesis. Bacterial attachment to the host ECM establishes a niche to grow and is considered one of the critical steps of infection. This pathogenic mechanism entails coordinated assembly of the ECM by the host to form the ECM structure and organization that are specifically recognized by bacteria for their adhesion. We serendipitously discovered that epithelial Sdc1 facilitates the assembly of FN fibrils in the corneal basement membrane and that this normal biological function of Sdc1 has detrimental consequences for the host in corneal infection. Our studies suggest that bacterial subversion of the host ECM is more complex than previously appreciated.