HSPGs in Alpha-toxin-induced Tissue Injury

细菌病原体阐述了一系列不同的毒素，这些毒素破坏了宿主组织的动态平衡。毒素 可以直接损害宿主细胞，但有几种可以通过失调宿主反应和引起 炎性组织损伤。此外，在许多传染病中，越来越多的证据表明 病原体的定植引发了疾病，但疾病的发展在很大程度上是由 寄主对感染的反应失调。这项R21提案的中心目标是探索肝素如何 硫酸盐蛋白多糖(HSPGs)调节宿主对金黄色葡萄球菌α毒素的应答 毒力因子与许多葡萄球菌疾病有关。我们在初步研究中发现Syndecan-1 Null(Sdc1-/-)小鼠在鼻腔攻击(I.N.)时表现出明显的炎性肺损伤。使用 金黄色葡萄球菌α毒素。Syndecan-1是肺II型上皮细胞的主要细胞表面热休克蛋白，α-毒素 是金黄色葡萄球菌肺炎的公认致病因子。重要的是，肺损伤的表型是 被I.N救了。给药纯化的Syndecan-1胞外区、硫酸乙酰肝素(HS)或硫酸化HS 片段，但不是由硫酸软骨素(CS)、不含HS和CS链的核心蛋白或低硫酸化HS 片段，表明Syndecan-1HS中的硫酸基结构域对α毒素诱导的肺损伤具有保护作用。 然而，使-1\f25 Syndecan-1\f25 HS-1以这种方式运行的关键结构特征和 Syndecan-1在α毒素所致肺损伤中的生物学靶点尚不清楚。这个项目将填补这些 通过精确定义HS硫酸盐化代码，使SDc1能够显著和具体地 抑制α毒素诱导的肺损伤(目标1)，并通过探索SDC1相互作用与先天免疫的作用 调节失调的宿主对α毒素反应中的细胞和细胞因子。最终目标是提供一个 热休克蛋白在毒素肺损伤中的分子、糖生物学和细胞学基础 细菌性肺炎新的诊断和治疗方法的发展。

Bacterial pathogens elaborate a diverse array of toxins that disrupt the homeostasis of host tissues. Toxins can directly damage host cells, but several enhance virulence by dysregulating the host response and causing inflammatory tissue injury. Furthermore, in many infectious diseases, accumulating evidence suggests that colonization of pathogenic organisms instigates disease, but disease progression is largely mediated by the dysregulated host response to infection. The central goal of this R21 proposal is to explore how heparan sulfate proteoglycans (HSPGs) modulate the host response to Staphylococcus aureus α-toxin, an exotoxin virulence factor implicated in many staphylococcal diseases. We found in preliminary studies that syndecan-1 null (Sdc1-/-) mice show significantly increased inflammatory lung injury when challenged intranasally (i.n.) with S. aureus α-toxin. Syndecan-1 is the major cell surface HSPG of type II epithelial cells in the lung, and α-toxin is an established virulence factor for S. aureus pneumonia. Importantly, the lung injury phenotypes were rescued by i.n. administration of purified syndecan-1 ectodomains, heparan sulfate (HS) or sulfated HS fragments, but not by chondroitin sulfate (CS), core protein devoid of HS and CS chains or low sulfated HS fragments, indicating that sulfated domains in syndecan-1 HS protect against α-toxin-induced lung injury. However, the critical structural features that enable syndecan-1 HS to function in this manner and the biological target of syndecan-1 in α-toxin-induced lung injury are unknown. This project will fill these mechanistic gaps by precisely defining the HS sulfation code that enables Sdc1 to prominently and specifically inhibit α-toxin-induced lung injury (aim 1), and by exploring the role of Sdc1 interactions with innate immune cells and cytokines in the dysregulated host response to α-toxin. The culminating goal is to provide a molecular, glycobiological, and cellular basis for HSPGs in toxin-induced lung injury for the translational development of new diagnostics and therapeutics for bacterial pneumonia.