Immune mechanisms of influenzaâÂÂinduced exacerbation of atherosclerosis

流感引起动脉粥样硬化恶化的免疫机制

• 批准号: 10455462
• 负责人: Radha Gopal
• 金额: $ 38.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455462
• 关键词: Antigen Presentation; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Vessels; Body Weight decreased; Bone Marrow; CCL2 gene; CCL3 gene; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cessation of life; Clinical; Color; Complication; Coronary Arteriosclerosis; Critical Care; Dendritic Cells; Development; Endothelial Cells; Epithelial; Epithelial Cells; Event; Foam Cells; Frequencies; Goals; Heart failure; High Fat Diet; Human; Immune; Immunotherapeutic agent; In Vitro; Incidence; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; Interferon Type II; Interferons; Interleukin-17; Interleukin-6; Knowledge; Label; Laboratories; Lipids; Lung; Lung diseases; Lymphoid; Morbidity - disease rate; Mus; Myelogenous; Myocardial Infarction; Oropharyngeal; Outcome; Pathogenesis; Pathologic; Patients; Phase; Play; Pneumonia; RANTES; Recovery; Reporting; Research; Risk; Role; Rupture; Series; Serum; Signal Transduction; Spleen; Stimulus; Stroke; T-Lymphocyte; Testing; Time; Vascular Endothelial Cell; Viral; Virus Replication; Weight Gain; adaptive immune response; bronchial epithelium; cardiovascular disorder risk; chemokine; cytokine; cytokine release syndrome; epidemiology study; flu; influenza infection; influenzavirus; insight; intraperitoneal; macrophage; mortality; mouse model; oxidized low density lipoprotein; pandemic influenza; recruit; therapeutic target; trafficking

Immune mechanisms of Influenza-induced exacerbation of atherosclerosis Influenza A infection is a significant cause of mortality and morbidity worldwide. It is estimated that 3-4 million cases of severe illness and 300,000 deaths due to influenza infection occur annually. During influenza pandemics, the focus is on lung disease, which is the most common cause of death. However, recent epidemiological studies reported significant mortality associated with cardiovascular diseases (CVD) during influenza infection. Atherosclerosis is a common cause of coronary artery disease (CAD), including MI, stroke, and heart failure. The innate and adaptive immune response to modified lipids and vascular endothelial cells causes a series of events that result in plaque formation in medium to large-sized arteries. If inflammatory stimuli continue, plaques become vulnerable to rupture and can cause MI. However, the mechanism involved in the influenza-induced increase in MI incidence is not clear. Our long-term research goal is to understand the impact of lung-vascular interactions in atherosclerosis. The objective of this application is to determine how influenza infection directly or indirectly impacts the outcome of atherosclerosis. In Aim 1, we will characterize myeloid and lymphoid cellular subsets from lung, aorta, and spleen at various time points (early, peak, recovery phase) after fluorescent-labeled (Color-flu) influenza infection to track influenza virus along with the cellular recruitment to the vessel. We will then examine whether antigen presentation is impacted by oxidized LDL (oxLDL) using bone marrow dendritic cells (BMDCs) and T cell re- stimulation in vitro. In Aim 2, we will determine the role of type III IFNs (IFNλ) systemically (intraperitoneal) or locally in the lung (oropharyngeal) in influenza-induced exacerbation of atherosclerosis. Further, we will determine the effect of IFNλ on foam cell formation in macrophages. Finally, we will determine the effect of conditioned media from influenza or type I (IFNβ), type II (IFNγ), and type III (IFNλ)-treated human bronchial epithelial cells (HBE) on human primary aortic endothelial cells (HAEC) to identify the mechanism involved in the lung-vascular interactions in atherosclerosis. In Aim 3, we will determine the effect of IL-17 neutralization systemically (intraperitoneal) or locally in the lung (oropharyngeal) in influenza induced-exacerbation of atherosclerosis. Further, we will determine the effect of lung epithelial IL-17RC signaling during influenza infection in atherosclerotic Apoe-/- mice. Finally, we will determine the effect of conditioned media from influenza- infected or IL-17-treated human bronchial epithelial cells (HBE) on vascular endothelial cells (HAEC) to identify the mechanism involved in the lung-vascular interactions in atherosclerosis. At the completion of these studies, we expect to have made mechanistic insights into the cellular trafficking, viral trafficking, systemic and local effects of IFNs and IL-17, and pulmonary epithelial IL-17 signaling in influenza-induced exacerbation of atherosclerosis that may help to identify immune-based therapeutic targets.

流感诱发动脉粥样硬化恶化的免疫机制 甲型流感感染是导致全世界 3-400 万人死亡和发病的重要原因。 每年因感染流感而导致重症病例和死亡人数达 30 万人。 在流行病中，重点是肺部疾病，这是最常见的死亡原因。 流行病学研究报告了与心血管疾病（CVD）相关的显着死亡率 流感感染是冠状动脉疾病（CAD）的常见原因，包括心肌梗死、中风、 对修饰脂质和血管内皮细胞的先天性和适应性免疫反应。 如果受到炎症刺激，会引起一系列事件，导致中型至大型动脉中形成斑块。 如果继续下去，斑块就会变得容易破裂并可能导致心肌梗塞，但是，其机制却很复杂。 流感引起的心肌梗死发病率增加尚不清楚。 我们的长期研究目标是了解肺-血管相互作用对动脉粥样硬化的影响。 该应用程序的目的是确定流感感染如何直接或间接影响结果 在目标 1 中，我们将描述肺、主动脉和脾脏的骨髓和淋巴细胞亚群的特征。 荧光标记（彩色流感）流感感染后的各个时间点（早期、高峰、恢复期） 跟踪流感病毒以及细胞招募到血管的情况，然后我们将检查抗原是否存在。 使用骨髓树突状细胞 (BMDC) 和 T 细胞重新表达，会受到氧化 LDL (oxLDL) 的影响 在目标 2 中，我们将确定 III 型干扰素 (IFNλ) 的全身（腹膜内）或体外刺激的作用。 流感引起的动脉粥样硬化恶化进一步发生在肺部（口咽部）。 确定 IFNλ 对巨噬细胞泡沫细胞形成的影响 最后，我们将确定 IFNλ 的影响。 来自流感或 I 型 (IFNβ)、II 型 (IFNγ) 和 III 型 (IFNλ) 处理的人支气管的条件培养基 上皮细胞（HBE）对人原代主动脉内皮细胞（HAEC）的影响，以确定参与的机制 在目标 3 中，我们将确定 IL-17 中和的作用。 全身（腹膜内）或局部肺部（口咽）流感引起的恶化 此外，我们将确定流感期间肺上皮 IL-17RC 信号传导的影响。 最后，我们将确定流感病毒条件培养基的作用。 在血管内皮细胞 (HAEC) 上感染或经 IL-17 处理的人支气管上皮细胞 (HBE) 来识别 在这些研究完成时，涉及动脉粥样硬化中肺-血管相互作用的机制。 我们期望对细胞运输、病毒运输、系统性和局部性的机制有深入的了解。 IFN 和 IL-17 以及肺上皮 IL-17 信号传导在流感诱导的病情恶化中的作用 动脉粥样硬化可能有助于确定基于免疫的治疗靶点。