Mechanisms of competitive displacement by lineages of mosquito-borne dengue virus

描述（由申请人提供）：四种血清型蚊媒登革热病毒（DENV-1-4）的感染呈上升趋势；目前估计，在大约100个国家，每年有近4亿人感染DENV。登革热的表现形式从亚临床感染到经典登革热再到严重疾病，包括登革出血热（DHF）和登革休克综合征（DSS）。在过去五十年中，严重登革热的范围和发病率急剧上升。在异型（第二血清型）继发感染期间，DHF/DSS的风险显著升高，DHF/DSS的增加在一定程度上可归因于特定地区多种血清型的共循环增加。然而，每一种登革热病毒血清型都包含多种基因型，这些基因型的核苷酸同一性差异为0.5%，而基因型又包含多种遗传上不同的谱系，这些谱系被称为毒株、枝或群体。DENV流行病学的一个日益普遍的特征是某一特定血清型的基因型或毒株侵入某一地区，并取代同一血清型的本地基因型或毒株。由于基因型和菌株在异型继发性感染或原发性感染期间引起DHF/DSS的倾向可能存在显著差异，因此谱系替换事件可能对受影响地区的疾病动态产生重大影响。很明显，DENV中很大比例的世系移位是由蚊子内在传染性的世系差异介导的，但一些世系实现更大蚊子传染性的机制尚未确定。我们先前研究了与斯里兰卡连续谱系迁移相关的三株DENV-3的传染性。1989年，登革出血热后的DENV-3毒株取代了登革出血热前的毒株，导致登革出血热病例激增。2000年，超DHF毒株取代了后DHF毒株，DHF发病率再次上升。我们已经表明，登革出血热后毒株比登革出血热前毒株更具传染性。但令人惊讶的是，超dhf菌株对伊蚊的传染性较弱。埃及伊蚊比登革出血热后菌株。基于在培养的蚊子细胞中具有或缺乏功能性RNA干扰（RNAi）反应的初步研究，提出的研究将验证这样一种假设，即病毒株与RNAi相互作用的差异导致DHF后菌株相对于DHF前菌株具有更大的传染性，而不是DHF后菌株具有更大的传染性

DESCRIPTION (provided by applicant): Infections with the four serotypes of mosquito-borne dengue virus (DENV-1-4) are one the rise; it is currently estimated that almost 400 million people are infected with DENV annually in approximately 100 countries. Dengue disease ranges in manifestation from subclinical infection to classical dengue fever to severe disease, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The range and incidence of severe dengue disease have risen dramatically in the last five decades. Risk of DHF/DSS is significantly elevated during a heterotypic (second serotype) secondary infection, and in part this increase in DHF/DSS is attributable in increasing co-circulation of multiple serotypes in a given locality. However each DENV serotype encompasses multiple genotypes, which differ by > 6% nucleotide identity, and genotypes in turn comprise multiple, genetically-distinct lineages, which have been termed strains, clades or groups. An increasingly common feature of DENV epidemiology is the invasion of a region by a genotype or strain of a given serotype and displacement of the native genotype or strain of that same serotype. Because genotypes and strains may differ significantly in their tendency to cause DHF/DSS during a heterotypic secondary infection or during primary infection, lineage replacement events can have a substantial impact on disease dynamics in the affected region. It is clear that a high proportion of lineage displacements in DENV are mediated by differences between lineages in intrinsic infectivity for mosquitoes, but the mechanisms by which some lineages achieve greater mosquito infectivity have not been identified. We have previously studied the infectivity of three strains of DENV-3 associated with consecutive lineage displacements in Sri Lanka. In 1989, the post-DHF strain of DENV-3 displaced the pre-DHF strain, resulting in a surge of DHF cases. In 2000, the ultra-DHF strain displaced the post-DHF strain, and DHF incidence rose again. We have shown that the post-DHF strain is more infectious than the pre-DHF strain for Ae. aegypti, but, surprisingly, that the ultra-DHF strain is less infectious for Ae. aegypti than the post-DHF strain. Building on preliminary studies in cultured mosquito cells that either possess or lack a functional RNA interference (RNAi) response, the proposed research will test the hypothesis that differences in virus strain interactions with RNAi account for the greater infectivity of the post- DHF strain relative to the pre-DHF strain but not for the greater infectivity of the post-DHF strain relative to the ultra-DHF strain. We will also seek, via transcriptome analysis, novel hypotheses for the mechanisms underpinning differences between the post-DHF and ultra-DHF strains. In the absence of a dengue vaccine or antiviral drugs, it is critical to understand the evolutionary drivers of DENV lineage displacement in order, eventually, to be able to identify and perhaps contain the spread of particularly dangerous DENV strains.