Chronic Ethanol Consumption and Pulmonary Immune Suppression

描述（由申请人提供）：众所周知，酗酒者呼吸道疾病的发病率增加。此外，慢性酒精中毒易导致呼吸道感染后的严重疾病。事实上，细菌性肺炎是这种易感性增加的最佳研究实例之一，与非酒精性肺炎患者相比，酒精性肺炎患者的死亡率高出2至7倍。酗酒还增加了与这类感染有关的发病率。虽然许多研究已经详细说明了酗酒者呼吸道感染期间疾病严重程度的增加，但对慢性乙醇（EtOH）消耗介导疾病严重程度增加的潜在机制或酒精如何改变肺部适应性免疫反应的了解要少得多。甲型流感病毒（IAV）感染代表了对人类健康的严重挑战，并且已知使个体易患肺炎的发病率增加。有趣的是，我们先前的研究表明，长期消费乙醇增加了流感相关的发病率和死亡率。此外，我们的结果表明，这种疾病严重程度的增加与呼吸道树突状细胞（rDC）以及流感特异性CD 8 T细胞应答的缺陷或改变有关。考虑到目前流行性和大流行性流感的威胁以及酗酒者链球菌感染的持续威胁，更好地了解酒精诱导的肺部适应性免疫反应中的病变可能会导致这些个体对这些重要人类病原体的免疫力增强的方法。因此，我们的长期目标是确定慢性EtOH在呼吸适应性免疫反应中诱导什么样的病变，并确定克服这些病变以防止严重和致命疾病的方法。在此应用程序中，我们将继续 使用Meadow-Cook慢性EtOH模型以及我们的流感病毒（IAV）和链球菌（GAS）感染的小鼠模型来实现这一目标。我们的中心假设是CD 8 T细胞内的缺陷是慢性EtOH小鼠呼吸道感染严重程度增加的原因。我们提出以下具体目标：目标1。确定针对IAV的疫苗接种是否可以增强CD 8 T细胞免疫并预防慢性EtOH消耗期间与IAV感染相关的增强的疾病;目的2。确定乙醇如何改变GAS或IAV+GAS感染期间肺部炎症的动力学、程度和特征以及CD 8 T细胞免疫。该应用不仅将定义IAV和GAS感染期间慢性EtOH在肺部适应性免疫中造成的缺陷，而且还应该增加我们对其他呼吸道感染期间存在慢性EtOH时免疫力的总体了解。此外，从这一应用中学到的见解有可能提出恢复和/或提高慢性酒精中毒者在这些疾病中的免疫力的方法。

DESCRIPTION (provided by applicant): It is well known that alcoholics have an increased incidence of respiratory diseases. Furthermore, chronic alcoholism predisposes for severe disease following respiratory infections. Indeed, bacterial pneumonias, among the best-studied examples of this increased predisposition, result in a 2 to 7-fold greater incidence in mortality i alcoholics compared to non-alcoholic pneumonia patients. Alcohol abuse additionally increases the morbidity associated with such infections. While many studies have detailed the increase in disease severity during respiratory infections in alcoholics, much less is understood about the underlying mechanisms through which chronic ethanol (EtOH) consumption mediates this increase in disease severity or how alcohol alters pulmonary adaptive immune responses. Influenza A virus (IAV) infections represent a serious challenge to human health and are known to predispose individuals to an increased incidence of pneumonia. Interestingly, our prior studies indicate that chronic consumption of EtOH increases both influenza associated morbidity and mortality. Further, our results suggest that this increased severity of disease is related to defects or alterations in both respiratory dendritic cells (rDC) as well as influenza- specific CD8 T cell responses. Given the current threat of both epidemic and pandemic influenza as well as the ongoing threat of Streptococcal infections in alcoholics a better understanding of the alcohol induced lesions within the pulmonary adaptive immune response could lead to methodologies to boost immunity to these important human pathogens in these individuals. Therefore our long-range goal is to determine what lesions chronic EtOH induces within the respiratory adaptive immune response and determine methodologies to overcome these lesions to protect from severe and fatal disease. Within this application we will continue to use the Meadow-Cook chronic EtOH model as well as our mouse models of influenza virus (IAV) and Streptococcus (GAS) infection toward this goal. Our central hypothesis is that defects within CD8 T cells are responsible for the increased severity of respiratory infections in chronic EtOH mice. We propose the following Specific Aims: Aim 1. Determine if vaccination against IAV can enhance CD8 T cell immunity and prevent the enhanced disease associated with IAV infections during chronic EtOH consumption; Aim 2. Determine how ethanol alters the kinetics, magnitude, character of pulmonary inflammation, and CD8 T cell immunity during GAS or IAV+GAS infections. This application will not only define the defects that chronic EtOH creates in pulmonary adaptive immunity during infections with IAV and GAS but should also increase our general understanding of immunity in the presence of chronic EtOH during other respiratory infections. Furthermore, the insights learned from this application hold the potential to suggest methodologies to restore and/or boost immunity in chronic alcoholics during these diseases.