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Chronic Ethanol Consumption and Pulmonary Immune Suppression

慢性乙醇消耗与肺部免疫抑制

基本信息

批准号：
8729464
负责人：
Kevin L Legge
金额：
$ 17.39万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-05 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729464
关键词：
Alcohol abuse Alcoholism Alcohols Bacteria Bacterial Infections Bacterial Pneumonia Bacteriophages CD8-Positive T-Lymphocytes CD8B1 gene Cellular Immunity Chronic Consumption Cytolysis Defect Dendritic Cells Development Disease Epidemic Ethanol Goals Health Human Immune Immune response Immunity Immunosuppression Immunosuppressive Agents Incidence Individual Infection Influenza Influenza A virus Ingestion Intervention Intestinal Mucosa Intravenous Iowa Kinetics Lead Learning Lesion Liver Lung Lung diseases Mediating Methodology Modeling Morbidity - disease rate Mus Nature Pathology Patients Pneumonia Predisposition Research Research Personnel Respiratory Mucosa Respiratory Tract Infections Severities Severity of illness Skin Spleen Streptococcal Infections Streptococcus Streptococcus pyogenes T cell response T-Lymphocyte Universities Vaccination Viral Virus Diseases adaptive immunity base chronic alcohol ingestion cooking expectation influenzavirus innovation insight intraperitoneal mortality mouse model non-alcoholic novel novel strategies pandemic influenza pathogen prevent problem drinker public health relevance research study respiratory subcutaneous

项目摘要

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.

描述（由申请人提供）：众所周知，酗酒者会增加呼吸道疾病的发病率。此外，慢性酒精中毒容易引发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充分研究的例子之一，导致酗酒者的死亡率比非酒精性肺炎患者高 2 至 7 倍。酗酒还会增加与此类感染相关的发病率。虽然许多研究详细介绍了酗酒者呼吸道感染期间疾病严重程度的增加，但人们对长期摄入乙醇 (EtOH) 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知之甚少。甲型流感病毒 (IAV) 感染对人类健康构成严重挑战，并且已知会增加个体肺炎发病率。有趣的是，我们之前的研究表明，长期摄入乙醇会增加流感相关的发病率和死亡率。此外，我们的结果表明，疾病严重程度的增加与呼吸树突状细胞 (rDC) 以及流感特异性 CD8 T 细胞反应的缺陷或改变有关。鉴于当前流行性和大流行性流感的威胁以及酗酒者中链球菌感染的持续威胁，更好地了解酒精引起的肺部适应性免疫反应损伤可能会导致找到增强这些个体对这些重要人类病原体的免疫力的方法。因此，我们的长期目标是确定慢性乙醇在呼吸道适应性免疫反应中诱发哪些病变，并确定克服这些病变以预防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 慢性乙醇模型以及我们的流感病毒 (IAV) 和链球菌 (GAS) 感染小鼠模型来实现这一目标。我们的中心假设是 CD8 T 细胞内的缺陷导致慢性 EtOH 小鼠呼吸道感染的严重程度增加。我们提出以下具体目标：目标 1. 确定 IAV 疫苗接种是否可以增强 CD8 T 细胞免疫力并预防慢性 EtOH 消耗期间与 IAV 感染相关的增强疾病；目标 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、特征以及 CD8 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产生的缺陷，而且还应增加我们对其他呼吸道感染期间慢性 EtOH 存在下的免疫的一般理解。此外，从该应用中获得的见解有可能提出在这些疾病期间恢复和/或增强慢性酗酒者免疫力的方法。