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

Abstract

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 in vivo. 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 Sdc1−/− corneas were significantly less susceptible to Streptococcus pneumoniae infection. Administration of excess Sdc1 ectodomains significantly inhibited S. pneumoniae corneal infection, suggesting that Sdc1 promotes infection as a cell surface attachment receptor. However, S. pneumoniae did not interact with Sdc1 and Sdc1 was shed upon S. pneumoniae infection, indicating that Sdc1 does not directly support S. pneumoniae adhesion. Instead, Sdc1 promoted S. pneumoniae adhesion by driving the assembly of fibronectin (FN) fibrils in the corneal basement membrane to which S. pneumoniae attaches when infecting injured corneas. S. pneumoniae specifically bound to corneal FN via PavA, and PavA deletion significantly attenuated S. pneumoniae virulence in the cornea. Excess Sdc1 ectodomains inhibited S. pneumoniae corneal infection by binding to the Hep II domain and interfering with S. pneumoniae PavA binding to FN. These findings reveal a previously unknown virulence mechanism of S. pneumoniae where key extracellular matrix (ECM) interactions and structures that are essential for host cell homeostasis are exploited for bacterial pathogenesis. IMPORTANCE 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 S. pneumoniae corneal infection. Our studies suggest that bacterial subversion of the host ECM is more complex than previously appreciated.

Chemical editing of proteoglycan architecture

“…SDC1 is an important PG that mediates myriad complex biological functions. When anchored at the cell surface, it can serve as a functional receptor for microbes (50) and cytokines, and promote the assembly of extracellular matrix components (51). Interestingly, when it is processed by matrix metalloproteinases or sheddases, the soluble ectodomains can carry out competing functions to membrane-anchored SDC1 (52).…”

Comparison of the Effects of Acute Appendicitis and Chronic Cholecystitis on Intestinal Mucosal Function During Surgery

“…Sdc-1 is also an early target molecule for many pathogenic bacteria. The loss of Sdc-1 as a result of genetic mutation reduces the susceptibility of mice to several bacterial infections [30]. Sdc1 is essential for maintaining a normal epithelial barrier.…”

Zur klinisch-pathologischen Korrelation der mikrobiellen Keratitis und darüber hinaus: Gibt es eine korneale Sepsis?

“…interleukin-17 [30] or macrophage migration inhibitory factor (MIF) [31] and extracellular structural molecules. Binding to heparan sulfate [32,33] and fibronectin molecules under the influence of syndecane-1 [34] may be important. In addition, pathogens such as Candida albicans, Pseudomonas and Serratia form enzymes, such as proteases, which damage both the extracellular matrix of the cornea as well as the immunoglobulins and the function of neutrophilic granulocytes [35,36].…”

“…B. Interleukin-17 [30] oder Macrophage Migration Inhibitory Factor (MIF) [31] und extrazellulärer Strukturmoleküle in der Lage, sich auszubreiten. Dabei können die Bindung an Heparansulfat [32,33] und Fibronektinmoleküle unter Beeinflussung von Syndecan-1 [34] wichtig sein. Zudem bilden Erreger wie Can-dida albicans, Pseudomonas und Serratia Enzyme, wie z.…”