Immune mechanisms of influenzaÃ¢ÂÂinduced exacerbation of atherosclerosis

流感引起动脉粥样硬化恶化的免疫机制

基本信息

批准号：
10686394
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
项目类别：
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/10686394
关键词：
Acceleration 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 Cells Epithelium Event Foam Cells Frequencies Goals Heart failure High Fat Diet Human IL17 gene Immune Immunotherapeutic agent In Vitro Incidence Infection Inflammation Mediators Inflammatory Inflammatory Response Influenza Influenza A virus Innate Immune Response Interferon Type I Interferon Type II Interferons Interleukin-6 Knowledge Label Laboratories Lipids Lung Lung diseases Lymphoid Macrophage 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 mortality mouse model oxidized low density lipoprotein pandemic influenza recruit therapeutic target trafficking

项目摘要

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.

流感诱导的动脉粥样硬化加重的免疫机制流感感染是全球死亡率和发病率的重要原因。据估计有3-400万每年因影响力感染而导致的严重疾病和300,000例死亡。在影响力期间大流行病的重点是肺部疾病，这是最常见的死亡原因。但是，最近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。动脉粥样硬化是冠状动脉疾病（CAD）的常见原因，包括MI，中风，和心力衰竭。对修饰的脂质和血管内皮细胞的先天和适应性免疫响应引起一系列事件，导致中等大小动脉形成牙菌斑。如果炎症性刺激继续，斑块变得容易破裂并可能导致MI。但是，涉及的机制流感引起的MI事件增加尚不清楚。我们的长期研究目标是了解肺血管相互作用在动脉粥样硬化中的影响。这该应用的目的是确定影响力直接或间接影响影响的结果动脉粥样硬化。在AIM 1中，我们将表征肺，主动脉和Sleen的髓样和淋巴样细胞子集在荧光标记（颜色 - 弗鲁）影响到的各个时间点（早期，峰值，恢复阶段）跟踪流感病毒以及血管的细胞募集。然后，我们将检查抗原是否使用骨髓树突状细胞（BMDC）和T细胞重复的氧化LDL（OXLDL）对表现产生了影响体外刺激。在AIM 2中，我们将系统（腹膜内）或在肺（口咽）流感诱导的动脉粥样硬化加剧的局部。此外，我们会的确定IFNλ对巨噬细胞中泡沫细胞形成的影响。最后，我们将确定来自影响力或I型（IFNβ），II型（IFNγ）和III型（IFNλ）处理的人支气管的条件培养基人类原发性主动脉内皮细胞（HAEC）上的上皮细胞（HBE）识别涉及的机制动脉粥样硬化中的肺血管相互作用。在AIM 3中，我们将确定IL-17谈判的影响全身（腹膜内）或局部在肺（口咽）流感诱导的诱导的外观动脉粥样硬化。此外，我们将确定影响力期间肺上皮IL-17RC信号的作用动脉粥样硬化apoe - / - 小鼠感染。最后，我们将确定来自影响力的条件培养基的影响在血管内皮细胞（HAEC）上感染或IL-17处理的人支气管上皮细胞（HBE）以鉴定动脉粥样硬化中肺血管相互作用涉及的机制。完成这些研究时，我们希望对细胞贩运，病毒贩运，全身和地方的机械见解做出见解 IFNS和IL-17，以及肺上皮IL-17信号传导流感诱导的加剧的影响动脉粥样硬化可能有助于鉴定基于免疫的治疗靶标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Immune Mechanisms in Cardiovascular Diseases Associated With Viral Infection.

DOI：
10.3389/fimmu.2020.570681
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Gopal R;Marinelli MA;Alcorn JF
通讯作者：
Alcorn JF

Sodium-Glucose Cotransporter-2 Inhibitor, Empagliflozin, Suppresses the Inflammatory Immune Response to Influenza Infection.

DOI：
10.4049/immunohorizons.2300077
发表时间：
2023-12-01
期刊：
ImmunoHorizons
影响因子：
0
作者：
Constantinesco NJ;Chinnappan B;DeVito LJ;Moras C;Srikanth S;Garcia-Hernandez ML;Rangel-Moreno J;Gopal R
通讯作者：
Gopal R

Zinc deficiency enhances sensitivity to influenza A associated bacterial pneumonia in mice.