Nipah Virus Pathobiology and Effects on Innate Immunity

尼帕病毒(Nipah Virus，NIV)是一种新出现的病毒病原体，被列为NIAID生物防御研究议程的C类病原体。新城疫病毒感染农业牲畜和人类；1999年，马来西亚和新加坡农业工人感染新城疫病毒导致40%的死亡率和价值超过1亿美元的牲畜损失。新城疫病毒是副粘病毒新属的一员，对新城疫病毒的生物学和免疫应答知之甚少。 然而，对新城疫患者的尸检研究发现，病毒的目标是淋巴结和内皮细胞，内皮合胞体的形成是新城疫感染的病理标志。细胞融合和合胞体的形成依赖于NIVF和G包膜糖蛋白的表达。我们发现，合胞体的形成是由这些包膜糖蛋白的糖基化调节的，其中NIV F和G上的特定N-糖链在细胞中发挥着重要作用 核聚变。重要的是，我们还发现Galectin-1可以阻止细胞融合，Galectin-1是一种由内皮细胞和树突状细胞表达的天然免疫系统的内源性凝集素。此外，我们还发现Galectin-1能诱导单核细胞来源的树突状细胞分泌强大的促炎细胞因子，这一作用可能增强抗病毒免疫反应。我们对这一提议的推动力假设是Niv F和G糖蛋白上的糖链结构。识别这些结构的先天免疫凝集素Galectin-1是这种病毒疾病发病机制中的关键决定因素。我们的具体目标是：(1)确定对糖蛋白表达和合胞体形成至关重要的F和G包膜糖蛋白上的寡糖的结构特征；(2)阐明Galectin-1调节NIV包膜糖蛋白介导的细胞融合的机制；(3) 描述与靶细胞结合和融合所涉及的结构特征，(4)检测Galectin-1对先天和获得性免疫反应的可溶性介质的影响。 这项工作将解决快速开发战略以增强对这种新出现的病毒病原体的先天免疫反应的关键问题。合作研究人员拥有独特的专业知识组合，并提出了一套关于新城疫发病机制的糖生物学的创新研究。

The Nipah virus (NiV) is an emerging viral pathogen, classified as a Category C pathogen of the NIAID Biodefense Research Agenda. NiV infects agricultural livestock and humans; in 1999, NiV infection among agricultural workers in Malaysia and Singapore resulted in a 40% mortality rate and loss of livestock worth over $100 million. NiV is a member of a new genus of paramyxoviruses, and little is known about NiV biology or the immune response to NiV. However, autopsy studies of NiV victims found that the virus targets lymph nodes and endothelial cells with endothelial syncytia formation being the pathologic hallmark of NiV infection. Cell fusion and syncytia formation depend on expression of the NiV F and G envelope glycoproteins. We have found that syncytia formation is regulated by glycosylation of these envelope glycoproteins, with specific N-glycans on NiV F and G playing important roles in cell fusion. Importantly, we have also found that cell fusion can be blocked by galectin-1, an endogenous lectin of the innate immune system that is expressed by endothelial cells and dendritic cells. In addition, we have made the novel observation that galectin-1 induces robust pro-inflammatory cytokine secretion by monocyte derived dendritic cells, an effect that may augment an antiviral immune response. Our driving hypothesis for this proposal is that glycan structures on the NiV F and G glycoproteins. and the innate immune lectin galectin-1 that recognizes these structures, are critical determinants in the pathogenesis of this viral disease. Our Specific Aims are: (1) Determine structural features of oligosaccharides on the F and G env glycoproteins that are critical for glycoprotein expression and syncytia formation, (2) Elucidate the mechanism by which galectin-1 regulates NiV envelope glycoprotein-mediated cell fusion, (3) Characterize the structural features involved in binding to and fusion of target cells, (4) Examine the effects of galectin-1 on soluble mediators of the innate and adaptive immune response. This work will address critical issues for rapid development of strategies to enhance innate immune responses to this emerging viral pathogen. The co-investigators have a unique combination of expertise, and propose an innovative set of studies into the glycobiology of NiV pathogenesis.