INTERFERON-ALPHA/BETA IN RESPIRATORY VIRUS PATHOGENESIS

呼吸道合胞病毒（RSV）是婴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。最初的感染通常发生在母体抗体存在的情况下，并且在整个生命过程中都会发生再次感染。迄今为止，研制安全有效疫苗的努力都失败了。20世纪60年代中期，在进行福尔马林灭活铝沉淀全病毒疫苗的试验期间，接种了疫苗的儿童的疾病增加，甚至致命，这一遗留问题阻碍了RSV疫苗开发的进展。缺乏对疫苗增强型RSV疾病的明确认识仍然阻碍了新疫苗在未感染RSV的婴儿中进行临床试验。我们的实验室已经证明，在对ifn - α / β （ifn - α / β受体-/-）或ifn - α / β和ifn - γ (Stat1-/-)没有反应的敲除小鼠株中，RSV和流感疾病的增强。这些突变动物的原发病毒感染病理类似于先前接种福尔马林灭活全病毒疫苗（FI-RSV）的小鼠RSV攻击后出现的加重的嗜酸性炎症和th -2样细胞因子模式。在本提案中，我们将验证我们的假设：RSV诱导IFN- α / β较差可能有助于解释FI-RSV疫苗制备诱导Th-2偏倚免疫。本提案的具体目的是：1)表征Stat1-/-小鼠对RSV感染的加重疾病反应。2) RSV免疫WT和突变动物的T细胞系分析。3)在IFN- α / β存在下引发RSV病理改变。4)开发一种促进强诱导IFN- α / β的疫苗策略。

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.