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: 7534917
• 负责人: THOMAS R JERRELLS
• 金额: $ 21.13万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534917
• 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; Numbers; 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; human TNF protein; migration; mouse model; respiratory; response

DESCRIPTION (provided by applicant): 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)-3. 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 R01 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（由申请人提供）：已证明人类和饮酒动物模型的酒精滥用与先天性和获得性免疫应答的抑制有关，这增加了对感染的易感性和致病性。与酗酒有关的较重要的传染病包括呼吸道感染。几个研究小组已经研究了实验动物肺部的细菌感染，但是关于长期饮酒对肺部病毒感染的影响的信息很少。我们建立了慢性饮酒和肺部病毒感染的动物模型。我们获得的初步数据支持这一建议，即长期饮酒与感染的严重程度增加有关。以下假设是根据初步数据提出的，并将在一个成熟的慢性（数月）饮酒动物模型和一个与人类肺部感染相关的病毒模型中进行检验。总体假设是，慢性酒精滥用导致呼吸道病毒感染的易感性和严重程度增加。在这个探索性/发展性赠款申请中提出的具体假设如下：1。慢性酒精消耗改变了对肺部病毒感染的早期（先天）免疫反应。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，这限制了干扰素（IFN）-3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，从而导致持续的肺部炎症。此外，不能通过IFN受体发出信号将限制感染的早期控制。2.长期饮酒会抑制获得性免疫应答，并偏向于T辅助细胞亚型2（TH 2）型应答，以限制抗原特异性CD 8 + T细胞的迁移或激活（或两者），从而清除肺部感染。这些作用的组合将抑制病毒感染的清除，从而增加肺部的炎症反应，以及可能增加慢性肺部疾病的发展机会，这将损害肺功能。从该探索性补助金申请中获得的数据将为进一步的机械R 01申请提供基础。最终，这条研究路线将产生关于酒精滥用对肺部病毒感染致病性的影响的重要信息，也许还有潜在的干预措施。与酒精滥用有关的一种更重要的传染病是呼吸道感染，但关于长期饮酒对肺部病毒感染的影响，获得的信息很少。由于与酒精滥用和酒精相关的肺部变化相关的免疫反应受到抑制，因此有理由认为呼吸道病毒感染的易感性增加。