Immune mechanisms of influenzaâÂÂinduced exacerbation of atherosclerosis

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一个重要原因。据估计，有300-400万人 每年都会发生因感染流感而导致的重症病例和30万人死亡。在流感期间 在大流行方面，重点放在肺部疾病上，这是最常见的死亡原因。然而，最近 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。动脉粥样硬化是导致冠状动脉疾病(CAD)的常见原因，包括心肌梗塞、中风、 和心力衰竭。对修饰脂质和血管内皮细胞的先天和获得性免疫反应 导致一系列事件，导致中到大型动脉形成斑块。如果炎性刺激 如果继续，斑块很容易破裂，并可能导致心肌梗死。然而，涉及的机制 流感导致的心肌梗死发病率的增加尚不清楚。 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。这个 此应用程序的目的是确定流感感染如何直接或间接影响 动脉硬化。在目标1中，我们将描述来自肺、主动脉和脾的髓系和淋巴系细胞亚群的特征。 在荧光标记(流感)感染后的不同时间点(早期、高峰、恢复期) 追踪流感病毒以及细胞对血管的募集。然后我们将检查抗原是否 氧化低密度脂蛋白(OxLDL)对骨髓树突状细胞(BMDCs)和T细胞再表达的影响 体外刺激。在目标2中，我们将系统地确定III型干扰素(干扰素λ)的作用。 局部在肺(口咽部)流行性感冒引起的动脉粥样硬化加重。此外，我们还将 测定干扰素λ对巨噬细胞泡沫细胞形成的影响。最后，我们将确定 来自流感或I型(干扰素β)、II型(干扰素γ)和III型(干扰素λ)处理的人支气管的条件培养液 上皮细胞(HBE)对人原代主动脉内皮细胞(HAEC)作用机制的研究 动脉粥样硬化中的肺-血管相互作用。在目标3中，我们将确定IL-17的中和效果 全身(腹膜内)或局部肺(口咽部)的流感诱导的恶化 动脉硬化。此外，我们将确定在流感期间肺上皮细胞IL-17RC信号的作用 动脉粥样硬化性APOE-/-小鼠的感染。最后，我们将确定条件培养液对流感的影响- 感染或IL-17处理的人支气管上皮细胞对血管内皮细胞的影响 动脉粥样硬化中肺-血管相互作用的机制。在这些研究完成后， 我们希望对手机贩运、病毒贩运、系统性和地方性的贩运有机械性的见解 干扰素和IL-17及肺上皮细胞IL-17信号转导在流感急性加重期的作用 动脉粥样硬化可能有助于确定基于免疫的治疗靶点。

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.