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。RSV引起的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，并且在整个生命过程中发生再感染。到目前为止，开发安全有效疫苗的努力都失败了。RSV疫苗开发的进展受到20世纪60年代中期福尔马林灭活、明矾沉淀的全病毒疫苗试验期间接种疫苗的儿童中增强的甚至致命的疾病的遗留影响的阻碍。对疫苗增强的RSV疾病缺乏明确的理解仍然阻碍着新疫苗在RSV初治婴儿中的临床试验。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-/-）无反应的敲除小鼠品系中，RSV和流感疾病增强。这些突变动物中原发性病毒感染的病理学类似于先前用福尔马林灭活的全病毒疫苗（FI-RSV）免疫的小鼠在RSV攻击后观察到的病理学，其具有加重的嗜酸性粒细胞炎症和Th-2样细胞因子模式。在本提案中，我们将检验我们的假设：RSV对IFN-α/β的不良诱导可能有助于解释FI-RSV疫苗制剂对Th-2偏向性免疫的诱导。本提案的具体目的是：1）表征Stat1-/-小鼠中响应RSV感染的加重疾病。2)来源于RSV免疫WT和突变动物的T细胞系的分析。3)在IFN-α/β存在下通过引发改变RSV病理学。4)促进IFN-α/β强诱导的疫苗策略的开发。

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.