ROLE OF TYPE III INTERFERONS IN STAPHYLOCOCCUS AUREUS RESPIRATORY TRACT INFECTION

摘要 金黄色葡萄球菌是人类呼吸道和流感的主要病原体。 感染是继发感染的主要易感因素。抗生素耐药性增加 是一个主要的问题，在没有保护性疫苗的情况下，了解细菌和 宿主在感染过程中将确定新的治疗目标。宿主的炎症过程 涉及金黄色葡萄球菌肺部感染的机制还不清楚，但我们已经确定了 III型干扰素途径在金黄色葡萄球菌感染时被激活。III型干扰素信号传导 有助于金黄色葡萄球菌在鼻咽和肺部的定植能力 导致过度免疫病理的急性肺炎。父母授予AIMS 为了描述导致金黄色葡萄球菌的III型干扰素背后的多种机制- 诱发疾病。目的1检测III型干扰素抑制中性粒细胞功能的能力和 他们的信号。目的2检测III型干扰素对炎症小体的影响。 在目标3中，这个通路的激活在不同的临床标本中是如何保守的 将被确定，并将检查与产生III型干扰素有关的主要细胞类型。 在这个少数补充剂的应用中，我们解决了上皮细胞参与引导 III型干扰素反应。使用体外系统和体内感染模型，我们将 确定上皮细胞如何参与：炎性细胞因子的产生，杀死S。 金黄色葡萄球菌及其对专业吞噬细胞功能的影响。在这些结束时 研究后，我们将扩大我们对III型IFN如何促进 金黄色葡萄球菌肺炎的发病机制，并将确定有针对性的机制 干扰素的产生对宿主免疫病理的治疗改善。

Summary Staphylococcus aureus is a major human pathogen of the respiratory tract and influenza co- infection is a major predisposing factor for subsequent infection. Increasing antibiotic resistance is a major concern and in the absence of a protective vaccine understanding the bacterial and host processes in infection will identify new treatment targets. The host inflammatory processes involved in S. aureus infection of the lung are not well understood, but we have identified the type III interferon pathway to be activated upon S. aureus infection. Type III interferon signaling contributes to the ability of S. aureus to colonize the nasopharynx as well as in the lung during acute pneumonia where they contribute to excessive immunopathology. The parents grant aims to delineate the multiple mechanisms behind type III interferons contributing to S. aureus- induced disease. Aim 1 examines the capacity of type III IFNs to inhibit neutrophil function and their signaling. In Aim 2 the capacity of type III IFN to influence the inflammasome is examined. In Aim 3 how conserved the activation of this pathway is across a variety of clinical specimens will be determined and the major cell types involved in producing type III IFN will be examined. In this minority supplement application we address the involvement of the epithelium in directing the type III interferon response. Using in vitro systems and in vivo models of infection we will determine how the epithelium contributes to: inflammatory cytokine production, killing of S. aureus and its influence over professional phagocyte function. At the conclusion of these studies, we will have expanded our knowledge on how type III IFNs contribute to the pathogenesis of S. aureus pneumonia, and will have identified targetable mechanisms for therapeutic amelioration of host immunopathology due to IFN production.