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: 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
• 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

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.

流感致动脉粥样硬化加重的免疫机制 甲型流感感染是世界范围内死亡和发病的重要原因。据估计，3-4百万 每年有30万人因感染流感而患重病和死亡。流感期间 在流行病中，重点是肺病，这是最常见的死亡原因。但最近的 流行病学研究报告了与心血管疾病（CVD）相关的显著死亡率， 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， 和心力衰竭修饰脂质和血管内皮细胞的天然和适应性免疫应答 引起一系列事件，导致中到大型动脉中的斑块形成。如果炎症刺激 如果斑块继续恶化，斑块变得容易破裂并可导致心肌梗死。然而， 流感引起的MI发病率增加尚不清楚。 我们的长期研究目标是了解动脉粥样硬化中肺血管相互作用的影响。的 本申请的目的是确定流感感染如何直接或间接影响 动脉粥样硬化在目标1中，我们将描述来自肺、主动脉和脾的髓样和淋巴样细胞亚群 在荧光标记（Color-flu）流感病毒感染后的不同时间点（早期、高峰期、恢复期）， 沿着流感病毒的细胞募集到血管中。然后我们将检查抗原 使用骨髓树突状细胞（BMDCs）和T细胞重建， 体外刺激。在目标2中，我们将确定III型IFN（IFNλ）的作用，全身（腹膜内）或 在流感引起的动脉粥样硬化恶化中局部存在于肺（口咽）。此外，我们将 测定IFNλ对巨噬细胞中泡沫细胞形成的影响。最后，我们将确定 来自流感病毒或I型（IFNβ）、II型（IFNγ）和III型（IFNλ）处理的人支气管炎的条件培养基 上皮细胞（HBE）对人主动脉内皮细胞（HAEC），以确定参与的机制， 动脉粥样硬化中肺血管的相互作用。在目标3中，我们将确定IL-17中和的作用。 在流感诱导的急性发作中全身（腹膜内）或局部（口咽） 动脉粥样硬化此外，我们将确定肺上皮细胞IL-17 RC信号转导在流感病毒感染期间的作用。 动脉粥样硬化Apoe-/-小鼠感染。最后，我们将确定流感条件培养基的效果- 感染的或IL-17处理的人支气管上皮细胞（HBE）在血管内皮细胞（HAEC）上，以鉴定 动脉粥样硬化中肺血管相互作用的机制。在完成这些研究后， 我们希望能对细胞运输、病毒运输、系统性和局部性的机制有深入的了解， IFN和IL-17以及肺上皮细胞IL-17信号转导在流感诱导的急性呼吸道综合征中的作用 动脉粥样硬化，这可能有助于识别基于免疫的治疗靶点。

项目成果

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
• 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.

• DOI: 10.14814/phy2.15902
• 发表时间: 2024-01
• 期刊: Physiological reports
• 影响因子: 2.5