INTERFERON-ALPHA/BETA IN RESPIRATORY VIRUS PATHOGENESIS

呼吸道合胞病毒(RSV)是婴幼儿和老年人下呼吸道感染的主要原因。呼吸道合胞病毒引起的毛细支气管炎和肺炎是6个月以下婴儿住院的主要原因。初次感染通常发生在母体抗体存在的情况下，再感染在一生中都会发生。到目前为止，开发安全有效的疫苗的努力都失败了。20世纪60年代中期，在福尔马林灭活、明矾沉淀的全病毒疫苗试验期间，接种疫苗的儿童患上了增强的、甚至致命的疾病，这阻碍了RSV疫苗开发的进展。缺乏对疫苗强化的RSV疾病的清楚了解仍然阻碍着RSV幼稚婴儿的新疫苗的临床试验。我们的实验室已经证明，在对干扰素-α/β(干扰素-α/β受体-/-)或干扰素-α/β和干扰素-γ(STAT1-/-)无效的基因敲除小鼠中，RSV增强和流感疾病。这些突变动物的原发病毒感染的病理与以前用福尔马林灭活全病毒疫苗(FI-RSV)免疫的小鼠在RSV攻击后看到的相似，具有加重的嗜酸性炎症和Th-2样细胞因子模式。在这项提案中，我们将检验我们的假设：RSV诱导较差的干扰素-α/β可能有助于解释FI-RSV疫苗制剂诱导Th-2偏向免疫的原因。这项建议的具体目标是：1)STAT1-/-小鼠因RSV感染而加重的疾病的特征。2)来自RSV免疫WT和突变动物的T细胞株的分析。(3)在干扰素-α/β刺激下，RSV的病理改变。4)发展疫苗策略，促进干扰素-α/β的强烈诱导。

Respiratory syncytial virus (RSV) is a major cause of lower respiratory infections in infants and the elderly. Bronchiolitis and pneumonia caused by RSV are the primary reasons for the hospitalization of infants under 6 months of age. The initial infection often occurs in the presence of maternal antibodies and reinfections occur throughout life. To date, efforts to develop a safe and effective vaccine have failed. Progress in RSV vaccine development has been hampered by the legacy of enhanced, even fatal, illness in vaccinated children during trials of a formalin- inactivated, alum-precipitated whole virus vaccine in the mid 1960s. The lack of a clear understanding of vaccine-augmented RSV disease still stands in the way of clinical trials of new vaccines in RSV naive infants. Our laboratory has demonstrated enhanced RSV and influenza disease in strains of knockout mice that are unable to respond to IFN-alpha/beta (IFN-alpha/beta Receptor-/-) or IFN-alpha/beta and IFN-gamma (Stat1-/- ). The pathology of primary virus infection in these mutant animals resembles that seen following RSV challenge of mice previously immunized with the formalin-inactivated whole virus vaccine (FI-RSV) with exacerbated, eosinophilic inflammation and a Th-2-like cytokine pattern. In this proposal we will test our hypothesis: that poor IFN- alpha/beta induction by RSV may help to explain the induction of Th-2 biased immunity by the FI-RSV vaccine preparation. The specific aims of this proposal are: 1) Characterization of exacerbated disease in response to RSV infection in Stat1-/- mice. 2) Analysis of T cell lines derived from RSV immune WT and mutant animals. 3) Alteration of RSV pathology by priming in the presence of IFN- alpha/beta. 4) Development of a vaccine strategy promoting strong induction of IFN- alpha/beta.