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: 9379264
• 负责人: Dane Parker
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379264
• 关键词: Activities of Daily Living; Acute Pneumonia; Antibiotic Resistance; Apoptosis; Biological Assay; Bone Marrow; Cell Line; Cells; Chemicals; Clinical; Community Hospitals; Confocal Microscopy; Dendritic Cells; Dependence; Disease; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Future; Human; IL8RB gene; Immunoblotting; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Influenza; Interferons; Interleukin-1 beta; Knock-out; Knowledge; Lead; Lung; MAP Kinase Gene; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Nasopharynx; Pathogenesis; Pathway interactions; Play; Pneumonia; Predisposing Factor; Process; Production; Quantitative Reverse Transcriptase PCR; Regulation; Reporter; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Role; Signal Pathway; Signal Transduction; Source; Specimen; Staining method; Stains; Staphylococcus aureus; Surface; Testing; Therapeutic; Therapeutic Intervention; Type III Epithelial Receptor Cell; Vaccines; antimicrobial; cell type; chemokine; co-infection; cytokine; humanized mouse; immunopathology; improved; improved outcome; in vivo Model; inhibitor/antagonist; interleukin-22; interleukin-23; killings; lung injury; macrophage; methicillin resistant Staphylococcus aureus; mortality; mouse model; neutralizing antibody; neutrophil; pathogen; respiratory; response; superinfection; synergism

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. This application will delineate the multiple mechanisms behind type III interferons contributing to S. aureus-induced disease. In Aim 1 we will investigate the influence of type III IFNs on neutrophil function and signaling and in Aim 2 we will examine their ability to influence the inflammasome. In Aim 3 we will determine how conserved activation of this pathway is across a variety of clinical specimens and identify the major cell types producing type III IFN. We will also examine the utility of IFN antibody neutralization in clearing infection under normal conditions and influenza co-infection, and in concert with current antimicrobials. We will utilize our recently developed humanized model of infection to confirm our observations in an improved model of infection. 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.

摘要 金黄色葡萄球菌是人类呼吸道和流感的主要病原体。 合并感染是继发感染的主要易感因素。越来越多的抗生素 耐药性是一个主要问题，在缺乏保护性疫苗的情况下 感染中的细菌和宿主过程将确定新的治疗目标。东道主 参与金黄色葡萄球菌肺部感染的炎症过程不是很好 了解，但我们已经确定了III型干扰素途径在S。 金黄色葡萄球菌感染。III型干扰素信号转导有助于金黄色葡萄球菌 在急性肺炎期间在鼻咽和肺内定植，在那里他们 导致过度的免疫病理反应。此应用程序将描述多个 III型干扰素导致金黄色葡萄球菌引起疾病的机制。在AIM 1我们将研究III型干扰素对中性粒细胞功能和信号的影响。 在目标2中，我们将检查它们影响炎症小体的能力。在《目标3》中，我们将 确定该通路在各种临床疾病中的保守激活程度 并确定产生III型干扰素的主要细胞类型。我们还将检查 干扰素抗体中和在正常条件下清除感染中的作用 流感合并感染，并与目前的抗菌药协同使用。我们将利用我们的 最近开发了人性化的感染模型，以证实我们在 改进的感染模型。在这些研究结束时，我们将扩大 我们对III型干扰素在金黄色葡萄球菌致病机制中的认识 肺炎，并将确定治疗改善的有针对性的机制 由于干扰素的产生而引起的宿主免疫病理改变。