Vector-driven selection in dengue virus

描述（由申请人提供）：近几十年来，登革热的全球大流行急剧升级，同时伴有更严重的登革热出血热（DHF）的增加。蚊媒登革热病毒（黄病毒属）是登革热的病原体，目前在100多个国家每年造成约1亿人感染，造成50万例登革出血热病例和2.5万人死亡。由于既没有获得许可的疫苗，也没有抗病毒治疗来控制登革热，因此迫切需要新的方法来控制这种新出现的疾病。然而，这些方法的合理发展需要更多关于登革热病毒-媒介相互作用演变的信息。具体而言，至关重要的是确定登革热病毒基因组中媒介驱动选择的目标，即基因组中影响登革热病毒感染其蚊子媒介的特异性和效率的那些区域。黄病毒共有80种，可分为三种不同传播方式的遗传谱系：(a)蚊媒传播，(b)蜱媒传播，(c)无已知媒介（假定直接传播）。在这些谱系之间的比较已经确定了在媒介传播的病毒和非媒介传播的病毒以及蜱传播的病毒和蚊子传播的病毒之间显示保守差异的序列区域。解释这种保守差异模式的三个假设是：(i)对传播方式的适应，（ii）对不同脊椎动物宿主的适应，（iii）非适应性系统发育惰性。拟议的研究将通过实验操纵登革热病毒3'非翻译区的保守差异区域来区分这些假设，以创建该区域已被(i)删除的病毒，（ii）被蜱传Langat病毒的同源序列所取代，（iii）被直接传播的莫多克病毒的同源序列所取代。将测试每种突变病毒感染蚊子和哺乳动物模型系统的能力。

DESCRIPTION (provided by applicant): The global pandemic of dengue fever has escalated dramatically in recent decades, accompanied by an increase in the more severe manifestation of the disease, dengue hemorrhagic fever (DHF). Mosquito-borne dengue virus (genus Flavivirus), the agent of dengue disease, currently causes an estimated 100 million infections per year in more than 100 countries resulting in 500,000 cases of DHF and 25,000 deaths. Since neither a licensed vaccine nor antiviral therapy is available to control dengue disease, new methods to control this emerging disease are urgently needed. However the rational development of these methods requires more information about the evolution of dengue virus-vector interactions than is currently available. Specifically, it is crucial to identify the targets of vector-driven selection in the dengue virus genome, i.e. those regions of the genome that affect the specificity and efficiency with which dengue virus infects its mosquito vectors. The 80 species of flaviviruses group into three genetic lineages that differ in their mode of transmission: (a) mosquito-borne, (b) tick-borne and (c) no known vector (assumed to be directly transmitted). Comparisons among these lineages have identified regions of sequence that show conserved differences between vector-borne and non-vector-borne viruses and between tick-borne and'mosquito-borne viruses. Three hypotheses to explain this pattern of conserved differences are: (i) adaptations for mode of transmission, (ii) adaptations for different sets of vertebrate hosts, (iii) non-adaptive phylogenetic inertia. The proposed research will distinguish among these hypotheses by experimentally manipulating regions of conserved difference in the dengue virus 3' untranslated region to create viruses in which the region had been (i) deleted, (ii) replaced with homologous sequence from tick-borne Langat virus, (iii) replaced with homologous sequence from directly-transmitted Modoc virus. Each mutant virus will be tested for its ability to infect mosquito and mammalian model systems.