Chronic Alcohol Alteration of Influenza-Specific CD8 T cell Immunity and Protection

 描述(申请人提供)：慢性酒精中毒会增加呼吸道疾病和感染的发病率和严重性。事实上，与非酗酒者相比，酗酒者在细菌性肺炎期间的死亡率和发病率都有所增加。虽然很多人都知道长期饮酒在增加呼吸道细菌严重程度方面所起的作用 关于慢性乙醇(Etoh)消费如何改变肺部病毒感染的严重程度，人们了解的要少得多。有趣的是，我们的研究表明，长期食用乙醇会增加流感病毒相关的发病率和死亡率。此外，我们的结果表明，这种疾病严重性的增加与流感特异性CD8 T细胞反应以及呼吸树突状细胞(RDC)的缺陷或改变有关。重要的是，我们使用Meadow-Cook乙醇消费模型发现的严重疾病和不良结局得到了最近一项人类研究的支持，该研究表明，在流感病毒感染期间，大量饮酒是严重后果的风险因素。因此，考虑到当前流行和潜在的大流行流感的威胁，更好地了解慢性酒精中毒患者肺适应性免疫反应中的损害可能导致提高这些人对这种重要人类病原体的免疫力的方法。我们的长期目标是确定慢性无水乙醇在呼吸适应性免疫反应中诱导了哪些损害。在这项应用中，我们将继续使用Meadow-Cook慢性Etoh模型以及我们的流感病毒感染小鼠模型，以确定Etoh诱导的环境与T细胞固有损伤在慢性Etoh肺部原发流感病毒感染期间CD8 T细胞免疫功能下降中的作用。此外，由于非免疫幼稚个体的CD8 T细胞反应由新的幼稚T细胞反应和现有的T细胞记忆组成，这一应用将是第一次确定慢性乙醇如何改变在慢性乙醇摄入之前已经建立的CD8 T细胞记忆。我们的中心假设是，慢性乙醇诱导的初级CD8T细胞反应的损伤是由环境和T细胞固有缺陷组成的，慢性乙醇将减少现有的CD8T细胞记忆。我们提出了以下具体目标：1)确定“环境”与T细胞内在因素对 乙醇诱导的初级IAV特异性CD8 T细胞反应的损伤，2)确定慢性酒精消费如何改变现有的流感特异性CD8 T细胞记忆和对流感病毒感染的异型保护。这一应用不仅将确定慢性无水乙醇在呼吸道病毒感染期间在肺适应性免疫中所造成的缺陷，而且也将增加我们对其他(细菌/真菌)呼吸道感染期间的免疫的了解。

 DESCRIPTION (provided by applicant): Chronic alcoholism increases the incidence and severity of respiratory diseases and infections. Indeed, alcoholics compared to non-alcoholic individuals have increased mortality and morbidity during bacterial pneumonias. While much is known about the role that chronic alcohol plays in increasing the severity of respiratory bacterial infections, much less is understood about how chronic ethanol (EtOH) consumption alters the severity of pulmonary virus infections. Interestingly, our studies indicate that chronic consumption of EtOH increases both influenza virus associated morbidity and mortality. Further, our results demonstrate that this increased severity of disease is related to defects or alteration in influenza-specific CD8 T cell responses as well as respiratory dendritic cells (rDC). Importantly our findings of severe disease and poor outcomes using the Meadows-Cook model of EtOH consumption have been supported by a recent study in humans which showed that heavy alcohol use is a risk factor for severe outcomes during influenza virus infections. Therefore given the current threat of both epidemic and potential pandemic influenza a better understanding of the lesions within the pulmonary adaptive immune response in chronic alcoholics could lead to methodologies to boost immunity to this important human pathogen in these individuals. Our long- range goal is to determine what lesions chronic EtOH induces within the respiratory adaptive immune response. Within this application we will continue to use the Meadow-Cook chronic EtOH model as well as our mouse models of influenza virus infection to determine the contributions of the EtOH induced environment vs. T cell intrinsic lesions in the reduced CD8 T cell immunity during primary influenza virus infections of the chronic EtOH lung. Further as the CD8 T cell response in non immunologically naive individuals is made up of both new naïve T cell responses as well as existing T cell memory, this application will be the first t determine how chronic EtOH alters CD8 T cell memory that has been established prior to chronic EtOH consumption. Our central hypothesis is that the chronic EtOH induced lesion in the primary CD8 T cell response is made up of both environmental and T cell intrinsic defects and that chronic EtOH will reduce existing CD8 T cell memory. We propose the following Specific Aims: 1) Determine the contribution of "environmental" vs. T cell intrinsic factors to the EtOH induced lesion in the primary IAV-specific CD8 T cell response, 2) Determine how chronic ethanol consumption alters existing influenza-specific CD8 T cell memory and heterosubtypic protection against influenza virus infections. This application will not only define the defects tht chronic EtOH creates in pulmonary adaptive immunity during respiratory virus infections but should also increase our understanding of immunity during other (bacterial/fungal) respiratory infections.