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Control of Influenza Infection by Lipid Mediators and Macrophages

通过脂质介质和巨噬细胞控制流感感染

基本信息

批准号：
10317033
负责人：
Young S. Hahn
金额：
$ 54.98万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317033
关键词：
Acute Respiratory Distress Syndrome Alveolar Alveolar Cell Alveolar Macrophages Anabolism Arachidonate 5-Lipoxygenase Asthma Cell Lineage Cells Cessation of life Core-Binding Factor Development Diffuse Disease Disease Outbreaks Dose Elderly Enzymes Epidemic Epithelial Cells Exhibits Family suidae Gene Expression Genes Human Immune Immune response Immune system In Vitro Individual Infection Infection prevention Influenza A Virus, H1N1 Subtype Influenza A virus Knockout Mice Laboratories Leukotriene Antagonists Leukotrienes Lower Respiratory Tract Infection Lower respiratory tract structure Lung Lung infections Measurable Mediating Metabolic Pathway Morbidity - disease rate Morphology Multiple Organ Failure Muramidase Mus Myelogenous Oxygen Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pneumonia Population Predisposition Process Property Pulmonary Inflammation Receptor Signaling Reporting Research Resistance Resistance to infection Respiratory System Respiratory Tract Diseases Role Severities Severity of illness Signal Transduction Speed T cell response Techniques Testing Tube Up-Regulation Upper respiratory tract Viral Pneumonia Virus Virus Replication Wild Type Mouse adaptive immune response age group airway epithelium alveolar epithelium base cell type conditional knockout cysteinyl leukotriene receptor cysteinyl-leukotriene defined contribution design experimental study human pathogen in vivo influenza infection influenza pneumonia influenzavirus lipid mediator lung injury macrophage macrophage product mortality mouse model novel pandemic disease prevent programs receptor respiratory tissue injury virus infection mechanism

项目摘要

Abstract Type A influenza virus (IAV) is a major human pathogen with the capacity to rapidly spread worldwide and to produce severe and sometimes fatal lung infections characterized by severe pneumonia. Disease severity resulting from IAV infection reflects the extent of virus replication in cells of the respiratory tract and the strength or magnitude of the host innate and adaptive immune response. Thus, the host immune response is not only responsible for IAV clearance but also contributes to tissue injury during infection. However, while the role of immune cells in virus elimination is well documented, the role of immune cells and in particular innate immune cells in regulating the susceptibility of respiratory tract cells in vivo to IAV infection is only poorly understood. We recently reported in a novel mouse model of IAV infection that upregulation of the cysteinyl leukotriene (5-lipoxygenase) metabolic pathway in terminal airway (alveolar) epithelial cells is associated with enhanced susceptibility of these cells to IAV infection. Furthermore, terminal airway resident (alveolar) macrophages suppress the upregulation of the 5-lipoxygenase pathway in terminal airway epithelial cells and as a consequence reduce the susceptibility of the cells to IAV infection. The program described in this application is designed to explore the role of the 5-lipoxygenase metabolic pathway and signaling via cysteinyl leukotriene receptors in controlling the susceptibility of airway epithelial cells to IAV infection and the mechanism by which terminal airway macrophages reduce susceptibility. We will establish the requirement for 5-lipoxygenase pathway enzymatic activity, cysteinyl leukotriene receptor signaling in terminal airway epithelial cells and explore the mechanism by which signaling through this receptor enhances susceptibility to IAV infection (Aim 1). In conjunction, we will explore the interaction between terminal airway macrophages, airway epithelial cells and IAV resulting in suppression of susceptibility of airway epithelial cells to infection, the mechanism of macrophage action leading to suppression and extend this analysis into the human (Aim 2).

摘要 A型流感病毒（IAV）是一种主要的人类病原体，能够在全球范围内迅速传播，产生严重的，有时是致命的肺部感染，其特征是严重的肺炎。疾病严重程度由IAV感染引起的感染反映了病毒在呼吸道细胞中复制的程度，宿主先天性和适应性免疫应答的强度或幅度。因此，宿主免疫应答是不仅负责IAV的清除，而且在感染过程中还导致组织损伤。然而，虽然免疫细胞在病毒清除中的作用是有据可查的，免疫细胞的作用，特别是先天免疫细胞，免疫细胞在调节体内呼吸道细胞对IAV感染的易感性方面的作用很差明白我们最近报道了一种新的IAV感染小鼠模型，终末气道（肺泡）上皮细胞中的白三烯（5-脂氧合酶）代谢途径与增强这些细胞对IAV感染的易感性。此外，终末气道驻留（肺泡）巨噬细胞抑制末端气道上皮细胞中5-脂氧合酶途径的上调，从而降低细胞对IAV感染的易感性。本文中描述的程序本申请旨在探索5-脂氧合酶代谢途径的作用和通过半胱氨酰的信号传导白三烯受体在控制气道上皮细胞对IAV感染的易感性中的作用，终末气道巨噬细胞降低易感性的机制。我们将制定以下要求： 5-终末气道上皮中的脂氧合酶途径酶活性、半胱氨酰白三烯受体信号传导细胞，并探索通过该受体的信号传导增强对IAV易感性的机制感染（目标1）。同时，我们将探讨终末气道巨噬细胞，气道炎症，上皮细胞和IAV导致气道上皮细胞对感染的易感性抑制，巨噬细胞作用导致抑制的机制，并将该分析扩展到人类（目的2）。