Effects of chronic alcohol consumption on pathogenesis of respiratory viral infec

长期饮酒对呼吸道病毒感染发病机制的影响

• 批准号: 7888583
• 负责人: THOMAS R JERRELLS
• 金额: $ 2.38万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888583
• 关键词: Address; Adult; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Animals; Antibody Formation; Antigens; Antiviral Agents; Applications Grants; Bacterial Infections; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Cell surface; Cells; Chronic; Chronic lung disease; Communicable Diseases; Data; Development; Exploratory/Developmental Grant; Failure; Helper-Inducer T-Lymphocyte; Human; Immune response; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Interferon Receptor; Interferon Type I; Interferons; Intervention; Lung; Lymphocyte Activation; Mediator of activation protein; Modeling; NK Cell Activation; Pathogenesis; Pathogenicity; Pneumonia; Predisposition; Production; Receptor Signaling; Respiratory Tract Infections; Respiratory physiology; Respiratory syncytial virus; Severities; Signal Transduction; Suggestion; T-Lymphocyte; Testing; Time; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Viral; Virus; Virus Diseases; alcohol effect; base; chemokine; chronic alcohol ingestion; cytokine; migration; mouse model; respiratory; response

DESCRIPTION Alcohol abuse by human beings and animal models of alcohol consumption have been shown to be associated with suppression of innate and acquired immune responses, which increases susceptibility to and pathogenicity of infections. Among the more important infectious diseases associated with alcohol abuse are respiratory infections. Several groups have investigated bacterial infections of the lungs of experimental animals, but little information has been obtained regarding the effects of chronic alcohol consumption on pulmonary viral infections. We have established an animal model of chronic alcohol consumption and pulmonary viral infection. The preliminary data we have obtained support the suggestion that chronic alcohol consumption is associated with increased severity of infection. The following hypotheses are proposed on the basis of the preliminary data and will be tested in a well-established animal model of chronic (months) alcohol consumption with a virus model relevant to pulmonary infections of human beings. The overarching hypothesis is that chronic alcohol abuse results in increased susceptibility to and severity of respiratory viral infections. Specific hypotheses addressed in this exploratory/developmental grant application are the following: 1. Chronic alcohol consumption alters the early (innate) immune responses to a pulmonary viral infection to A. limit early control of viral infection by suppressing activation of natural killer cells, which limits production of interferon (IFN)-¿. B. increase production of proinflammatory cytokines and chemokines. The continued viral infection would result in sustained production of these mediators, resulting in continued pulmonary inflammation. Further, failure to signal through the IFN receptor would limit the early control of the infection. 2. Chronic alcohol consumption suppresses the acquired immune response and biases to a T helper cell subtype 2 (TH2)type response to limit migration or activation (or both) of antigen-specific CD8+ T cells to clear infection in the lungs. A combination of these effects would inhibit clearance of the viral infection and, thus, increase the inflammatory response in the lungs, as well as possibly increase the chances of development of chronic lung disease, which would impair lung function. The data obtained from this exploratory grant application would provide the basis for a further mechanistic RO1 application. Ultimately, this line of study would yield important information regarding the effects of alcohol abuse on the pathogenicity of pulmonary viral infections and, perhaps, potential interventions. One of the more important infectious diseases associated with alcohol abuse are respiratory infections, but there have been little information obtained regarding the effects of chronic alcohol consumption on pulmonary viral infections. Because of the suppression of the immune response associated with alcohol abuse and alcohol-associated changes in the lung, it is reasonable to suggest increased susceptibility to respiratory viral infections.

描述 人类的酒精滥用和酒精消费的动物模型已经被证明与 先天性和获得性免疫反应受到抑制，这增加了对 感染的致病性。与酗酒有关的重要传染病包括 呼吸道感染几个小组已经研究了实验动物肺部的细菌感染， 动物，但很少有资料已获得关于慢性酒精消费的影响， 肺部病毒感染我们建立了慢性饮酒的动物模型， 肺部病毒感染我们获得的初步数据支持这样一种观点， 消费与感染严重程度的增加有关。提出了以下假设： 根据初步数据，并将在一个完善的慢性（月）酒精动物模型中进行测试 与人类肺部感染相关的病毒模型一起食用。 首要的假设是，慢性酒精滥用导致增加的易感性， 呼吸道病毒感染的严重程度。本文中提出的具体假设 探索性/发展性赠款申请如下： 1.慢性饮酒改变了对肺病毒的早期（先天）免疫反应 感染 A.通过抑制自然杀伤细胞的激活来限制病毒感染的早期控制， 干扰素（IFN）的产生。 B。增加促炎细胞因子和趋化因子的产生。持续的病毒感染 将导致这些介质的持续产生，导致持续的肺 炎症此外，不能通过IFN受体发出信号将限制对肿瘤的早期控制。 感染 2.长期饮酒抑制获得性免疫反应并偏向T辅助细胞 细胞亚型2（TH 2）限制抗原特异性CD 8 + T细胞迁移或活化（或两者）的型应答 细胞来清除肺部感染 这些作用的组合将抑制病毒感染的清除，并因此增加免疫应答。 肺部的炎症反应，以及可能增加发展的机会， 慢性肺部疾病，这会损害肺功能。 从该探索性补助金申请中获得的数据将为进一步的机械RO 1提供基础 应用程序.最终，这项研究将产生关于酒精影响的重要信息。 滥用对肺部病毒感染的致病性，也许，潜在的干预措施。与酗酒有关的一种重要传染病是 呼吸道感染，但获得的信息很少 长期饮酒对肺部病毒感染的影响。 因为酒精会抑制免疫反应 滥用和酒精相关的肺部变化，这是合理的建议 增加呼吸道病毒感染的易感性。