Effects of chronic alcohol consumption on pathogenesis of respiratory viral infec

描述（由申请人提供）：人类和动物饮酒模型的酒精滥用已被证明与先天和获得性免疫反应的抑制有关，这增加了对感染的易感性和致病性。与酒精滥用有关的更重要的传染病是呼吸道感染。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。我们建立了慢性酒精消耗和肺部病毒感染的动物模型。我们获得的初步数据支持长期饮酒与感染严重程度增加有关的建议。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）饮酒动物模型中与人类肺部感染相关的病毒模型中进行检验。最重要的假设是，长期酗酒会增加呼吸道病毒感染的易感性和严重程度。在这个探索性/发展性拨款申请中提出的具体假设如下：慢性饮酒改变了早期（先天）对肺部病毒感染的免疫反应，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。持续的病毒感染会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. 慢性饮酒抑制获得性免疫反应，并倾向于T辅助细胞亚型2 （TH2）型反应，以限制抗原特异性CD8+ T细胞的迁移或激活（或两者兼而有之），以清除肺部感染。这些影响的组合将抑制病毒感染的清除，从而增加肺部的炎症反应，并可能增加慢性肺部疾病的发展机会，这将损害肺功能。从这个探索性拨款申请中获得的数据将为进一步的机械R01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以及可能的干预措施的重要信息。与酒精滥用有关的更重要的传染病之一是呼吸道感染，但关于长期饮酒对肺部病毒感染的影响的信息很少。由于与酒精滥用和酒精相关的肺部变化相关的免疫反应的抑制，有理由认为呼吸道病毒感染的易感性增加。

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.