GPI anchored forms of the dengue virus NS1 protein: production and role in pathogenesis

登革热病毒由蚊子携带，在世界各地感染数百万人，特别是在东南亚、中美洲和南美洲、非洲的热带国家，最近在澳大利亚(北昆士兰和新界)。目前还没有疫苗或药物来预防或治疗感染，感染的特点是严重的疾病，包括炎症和发烧，有时可能是致命的。这项研究的重点是我们已经确定的一种不寻常的登革热病毒蛋白(称为NS1)。我们计划研究这种蛋白在更严重且往往是致命的登革热感染形式(登革热出血热和登革热休克综合征)中所起的作用。在这些更严重和危及生命的登革热形式中，这些患者的血管变得漏水。据认为，这是由感染细胞分泌某些化学物质(细胞因子)引起的。我们已经证明，感染登革热的人类细胞表面有一种不寻常的NS1蛋白，能够被抗体激活。抗体是人体为抵抗感染而产生的蛋白质。我们的目标是研究以这种方式激活的受感染的人类血细胞是否会分泌细胞因子，以及这些细胞因子是否会导致血管泄漏。我们还将研究病毒如何在病毒感染的两个宿主物种--蚊子和人类--中产生这种变种的NS1。这些研究将增加我们对登革病毒感染的了解，并将提供关于这种不寻常形式的登革病毒蛋白NS1在严重形式的登革热、登革出血热和登革休克综合征中所起作用的宝贵信息。

Dengue viruses are carried by mosquitoes and infect millions of people around the world, particularly in tropical countries of SE Asia, Central and South America, Africa and recently in Australia (North Queensland and NT). There is no vaccine or drug available for preventing or treating the infections, which are characterised by severe illness that involves inflammation and fevers that can sometimes be fatal. This study focuses on an unusual form of a dengue virus protein (called NS1) which we have identified. We plan to study the role that this protein plays in the more severe and often fatal forms of dengue infection (dengue haemorrhagic fever and dengue shock syndrome). In these more severe and life threatening forms of dengue the blood vessels of these patients become leaky. It is thought that this is caused by the secretion of certain chemicals (cytokines) from infected cells. We have shown that dengue infected human cells, which have the unusual form of NS1 protein on their surface, are capable of being activated by antibodies. Antibodies are proteins which are produced by the human body to fight infection. We aim to study whether cytokines are secreted from infected human blood cells activated in this way and whether these cytokines cause blood vessels to become leaky. We will also study how the virus produces this variant form of NS1 in the two host species that the virus infects; mosquito and human. These studies will increase our understanding of dengue virus infection and will provide valuable information concerning the role that this unusual form of the degue virus protein NS1 plays in the severe forms of dengue fever; dengue haemorrhagic fever and dengue shock syndrome.