Vector-driven selection in dengue virus

描述(申请人提供)：近几十年来，全球登革热大流行急剧升级，同时登革热更严重的表现形式--登革出血热(DHF)也有所增加。蚊媒登革病毒(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，导致500 000例登革出血热病例和25 000人死亡。由于既没有获得许可的疫苗也没有抗病毒疗法来控制登革热疾病，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比目前可用的更多关于登革热病毒-媒介相互作用进化的信息。具体而言，至关重要的是确定登革病毒基因组中媒介驱动选择的目标，即基因组中影响登革病毒感染其蚊子媒介的特异性和效率的区域。这80种黄病毒分成三种不同的遗传谱系，它们的传播方式不同：(A)蚊媒，(B)壁虱传播，(C)未知媒介(假定为直接传播)。对这些谱系的比较已经确定了序列的区域，这些区域显示了媒介传播的和非媒介传播的病毒之间以及扁虱传播的病毒和蚊媒传播的病毒之间的保守差异。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)非适应性系统发育惯性。这项拟议的研究将通过实验操作登革热病毒3‘非翻译区的保守差异区来区分这些假说，以创建其中该区域已被(I)删除，(Ii)替换为来自壁虱传播的朗加特病毒的同源序列，(Iii)替换为来自直接传播的莫多克病毒的同源序列的病毒。每种突变病毒都将被测试其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.