Abstract
Heparan sulfate proteoglycans (HSPGs) are at the forefront of host-microbe interactions. Molecular and cell-based studies suggest that HSPG-pathogen interactions promote pathogenesis by facilitating microbial attachment and invasion of host cells. However, the specific identity of HSPGs, precise mechanisms by which HSPGs promote pathogenesis, and the in vivo relevance of HSPG-pathogen interactions remain to be determined. HSPGs also modulate host responses to tissue injury and inflammation, but functions of HSPGs other than facilitating microbial attachment and internalization are understudied in infectious disease. Here we examined the role of syndecan-1 (Sdc1), a major cell surface HSPG of epithelial cells, in mouse models of Listeria monocytogenes (Lm) infection. We show that Sdc1-/- mice are significantly less susceptible to both intragastric and intravenous Lm infection compared to wild type (Wt) mice. This phenotype is not seen in Sdc3-/- or Sdc4-/- mice, indicating that ablation of Sdc1 causes a specific gain of function that enables mice to resist listeriosis. However, Sdc1 does not support Lm attachment or invasion of host cells, indicating that Sdc1 does not promote pathogenesis as a cell surface Lm receptor. Instead, Sdc1 inhibits the clearance of Lm before the bacterium gains access to its intracellular niche. Large intravascular aggregates of neutrophils and neutrophil extracellular traps (NETs) embedded with antimicrobial compounds are formed in Sdc1-/- livers, which trap and kill Lm. Lm infection induces Sdc1 shedding from the surface of hepatocytes in Wt livers, which is directly associated with the decrease in size of intravascular aggregated NETs. Furthermore, administration of purified Sdc1 ectodomains or DNase inhibits the formation of intravascular aggregated neutrophils and NETs and significantly increases the liver bacterial burden in Sdc1-/- mice. These data indicate that Lm induces Sdc1 shedding to subvert the activity of Sdc1 ectodomains to inhibit its clearance by intravascular aggregated NETs.
Highlights
Microbial attachment and invasion of host cells are necessary steps in the establishment of infection [1]
We initially hypothesized that if Listeria monocytogenes (Lm) exploits the syndecan family of Heparan sulfate proteoglycans (HSPGs) for its pathogenesis, hosts without syndecans will respond differently to Lm infection
Sdc1 is predominantly expressed by epithelial cells and plasma cells, Sdc2 is expressed by endothelial cells and fibroblasts, Sdc3 is expressed by neural crest-derived cells, and Sdc4 is expressed by most cell types, albeit at levels much lower than that of other syndecans [5, 24]
Summary
Microbial attachment and invasion of host cells are necessary steps in the establishment of infection [1]. A large number of viruses, bacteria, and parasites bind to the heparan sulfate (HS) moiety of HSPGs, and these interactions have been shown to facilitate pathogen attachment and invasion of host cells in vitro [2,3,4]. Cell surface HSPGs are thought to function primarily as coreceptors for heparin-binding microbial pathogens by localizing and increasing the concentration of pathogens at the host cell surface, thereby facilitating the interaction of pathogens with their respective signaling receptors. Current understanding of the role of HSPGs in infection is based predominately on in vitro systems. These studies advocate that HSPGs promote infection as an attachment and internalization receptor, but there are surprisingly very few supportive examples of this idea in vivo. HSPGs are multi-functional molecules, most studies have so far focused on their role as an attachment/internalization receptor, and have largely overlooked the possibility that HSPGs may have other functions in microbial pathogenesis
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