Department of Medicine, Boston Children's Hospital, Boston, MA, United States of America.
Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America.
PLoS Pathog. 2020 May 26;16(5):e1008497. doi: 10.1371/journal.ppat.1008497. eCollection 2020 May.
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.
硫酸乙酰肝素蛋白聚糖（HSPGs）是宿主-微生物相互作用的前沿领域。基于分子和细胞的研究表明，HSPG-病原体相互作用通过促进微生物附着和宿主细胞入侵来促进发病机制。然而，HSPGs 的具体身份、HSPG 促进发病机制的确切机制以及 HSPG-病原体相互作用的体内相关性仍有待确定。HSPGs 还调节宿主对组织损伤和炎症的反应，但 HSPGs 促进微生物附着和内化以外的功能在传染病中研究较少。在这里，我们研究了主要存在于上皮细胞表面的 HSPG 之一 syndecan-1（Sdc1）在李斯特菌（Lm）感染的小鼠模型中的作用。我们发现，与野生型（Wt）小鼠相比，Sdc1-/- 小鼠对胃内和静脉内 Lm 感染的敏感性明显降低。这种表型在 Sdc3-/- 或 Sdc4-/- 小鼠中没有出现，表明 Sdc1 的缺失导致了一种特定的功能获得，使小鼠能够抵抗李斯特菌病。然而，Sdc1 并不支持 Lm 附着或宿主细胞的入侵，这表明 Sdc1 不作为细胞表面 Lm 受体促进发病机制。相反，Sdc1 抑制了 Lm 在进入其细胞内小生境之前的清除。大量富含中性粒细胞的血管内大聚集体和嵌入抗菌化合物的中性粒细胞胞外陷阱（NETs）在 Sdc1-/- 肝脏中形成，这些聚集体捕获并杀死 Lm。Lm 感染诱导 Wt 肝脏肝细胞表面 Sdc1 的脱落，这与血管内聚集的 NETs 体积减小直接相关。此外，纯化的 Sdc1 外显子或 DNase 的给药抑制了血管内聚集的中性粒细胞和 NETs 的形成，并显著增加了 Sdc1-/- 小鼠肝脏的细菌负荷。这些数据表明，Lm 诱导 Sdc1 脱落以颠覆 Sdc1 外显子的活性，从而抑制其被血管内聚集的 NETs 清除。
