ROLE OF TYPE III INTERFERONS IN STAPHYLOCOCCUS AUREUS RESPIRATORY TRACT INFECTION

III 型干扰素在金黄色葡萄球菌呼吸道感染中的作用

• 批准号: 9766802
• 负责人: Dane Parker
• 金额: $ 5.07万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766802
• 关键词: Acute Pneumonia; Address; Antibiotic Resistance; Cell physiology; Clinical; Disease; Epithelial Cells; Epithelium; Exposure to; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Influenza; Interferons; Investigation; Knowledge; Lung; Lung infections; Minority; Nasopharynx; Pathogenesis; Pathway interactions; Phagocytes; Pneumonia; Predisposing Factor; Process; Production; Respiratory System; Respiratory Tract Infections; Signal Transduction; Specimen; Staphylococcus aureus; Staphylococcus aureus infection; System; Therapeutic; Vaccines; cell type; co-infection; cytokine; human pathogen; immunopathology; in vivo Model; neutrophil; parent grant; pathogen; response

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.

总结 金黄色葡萄球菌是人类呼吸道和流感共同的主要病原体， 感染是随后感染的主要诱发因素。抗生素耐药性增加 是一个主要的问题，在缺乏保护性疫苗的情况下， 感染中的宿主过程将确定新的治疗目标。宿主的炎症过程 参与了S.金黄色葡萄球菌感染的肺部还没有得到很好的理解，但我们已经确定， III型干扰素途径在S.金黄色葡萄球菌感染。III型干扰素信号传导 有助于S的能力。金黄色葡萄球菌在鼻咽和肺中定殖， 急性肺炎，它们导致过度的免疫病理学。家长资助的目标 描述III型干扰素导致S.金黄色， 诱发疾病。目的1检测III型IFN抑制中性粒细胞功能的能力， 他们的信号。在目的2中，检测III型IFN影响炎性小体的能力。 在目标3中，该途径的激活在各种临床标本中是如何保守的 将确定并检查参与产生III型IFN的主要细胞类型。 在这个少数补充申请中，我们讨论了上皮细胞参与指导 III型干扰素反应。使用体外系统和体内感染模型，我们将 确定上皮细胞如何促进：炎性细胞因子的产生，S. 金黄色葡萄球菌及其对专职吞噬细胞功能的影响。在这些结束时， 研究，我们将扩大我们的知识，如何III型干扰素有助于 致病性S.金黄色葡萄球菌肺炎，并将确定有针对性的机制， 由于IFN的产生而引起的宿主免疫病理学的治疗性改善。