EVOLUTIONARY CONSEQUENCES OF DENGUE VIRUS EMERGENCE

登革热病毒出现的进化后果

• 批准号: 7720452
• 负责人: Kathryn Alyce Hanley
• 金额: $ 6.31万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720452
• 关键词: Aedes; Africa; Arboviruses; Asia; Cells; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Culicidae; Dengue; Dengue Virus; Disease Outbreaks; Epidemic; Exclusion; Flavivirus; Funding; Grant; Human; Infection; Institution; Life; Life Cycle Stages; Measures; Mentors; Methods; Modeling; Pattern; Preparation; Productivity; Public Health; Relative (related person); Research; Research Personnel; Resources; Sequence Homology; Serotyping; Source; Testing; United States National Institutes of Health; Virus; Virus Replication; forest; in vivo; member; nonhuman primate; prevent; superinfection; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dengue virus (genus Flavivirus) the most significant threat to public health among the arthropod-borne viruses, circulates in two distinct life cycles. Epidemic dengue viruses, which cause human dengue fever, cycle between humans and peridomestic Aedes mosquitoes. Sylvatic dengue viruses cycle in the forest canopies of Africa and Asia between sylvatic Aedes species and non-human primates. Endemic and sylvatic viruses show high sequence homology, but sylvatic viruses do not cause outbreaks in humans. Our initial hypothesis to explain this apparent paradox was that an "adaptive barrier" prevents the emergence of sylvatic dengue virus, or more specifically that sylvatic dengue virus replicates poorly in either humans or in peridomestic Aedes species. However, in collaboration with INBRE mentor Scott Weaver (UTMB) and members of his lab, we have demonstrated that no such adaptive barrier exists, because sylvatic and endemic strains of DENV serotype 2 (DENV-2) are equally infectious for models of virus replication in humans (Vasilakis et al. 2007, Vaslakis et al. submitted, Vasilakis et al. in preparation) and for Ae. aegypti, the primary vector of endemic dengue (Hanley et al. in preparation). An alternative explanation for the restriction of sylvatic dengue to the forest cycle is that competition with endemic strains of DENV prevents emergence of sylvatic strains. Thus, our current research focuses on characterizing the strength and symmetry of competition between endemic and sylvatic DENV strains. Such competition could occur in either the host or vector, but may be more likely in the vector where infection persists for life. We have recently demonstrated that when mixed infections of DENV-2 and DENV-4 are introduced to cultured mosquito cells concurrently (co-infection) or with a designated interval between the introduction of the first and second serotype (superinfection), the replication of each serotype is decreased, as is the overall productivity of the infection (Pepin et al. in press, Pepin and Hanley in preparation). Moreover suppression is strongest for strains that infect second in superinfection treatments. These patterns are the hallmarks of competition. In the proposed research, patterns of competition between DENV-2 and DENV-4 will be tested in mosquitoes in vivo. Subsequently, we will use the same methods to measure competitive suppression of a panel of sylvatic and endemic DENV-2 isolates in vivo. Competitive suppression will be measured as the titer achieved by a particular isolate when it is co-infected with a common DENV-4 competitor versus when it infects alone. The relative competitive suppression of sylvatic and endemic isolates will be compared. If sylvatic isolates are poorer competitors against endemic DENV-4 than other endemic isolates, this will support the hypothesis that competition may contribute to the exclusion of sylvatic DENV from the endemic cycle.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 登革热病毒（黄病毒属）是节肢动物传播的病毒中对公共健康最严重的威胁，以两个不同的生命周期传播。 引起人类登革热的流行性登革热病毒在人类和家周围的伊蚊之间循环。 森林登革热病毒在非洲和亚洲的森林冠层中在森林伊蚊和非人类灵长类动物之间循环。 地方性病毒和森林病毒表现出高度的序列同源性，但森林病毒不会在人类中引起爆发。我们解释这一明显悖论的最初假设是，“适应性屏障”阻止了森林登革热病毒的出现，或者更具体地说，森林登革热病毒在人类或周围伊蚊物种中复制不良。然而，通过与 INBRE 导师 Scott Weaver (UTMB) 及其实验室成员的合作，我们证明了不存在这种适应性障碍，因为 DENV 血清型 2 (DENV-2) 的森林和地方性毒株对于人类病毒复制模型具有同等的传染性（Vasilakis 等人，2007 年，Vaslakis 等人提交，Vasilakis 等人正在准备）和 艾。埃及伊蚊，地方性登革热的主要媒介（Hanley 等人正在准备中）。 对森林登革热对森林循环的限制的另一种解释是，与登革热病毒地方性菌株的竞争阻止了森林登革热菌株的出现。因此，我们目前的研究重点是表征地方性和森林化登革病毒毒株之间竞争的强度和对称性。这种竞争可能发生在宿主或载体中，但更有可能发生在感染终生持续的载体中。我们最近证明，当同时将 DENV-2 和 DENV-4 的混合感染引入培养的蚊子细胞（共同感染）或在引入第一和第二血清型之间指定间隔（重复感染）时，每种血清型的复制都会减少，感染的总体生产力也会减少（Pepin 等人正在出版，Pepin 和 Hanley 正在准备）。 此外，对重复感染治疗中第二次感染的菌株的抑制作用最强。这些模式是竞争的标志。在拟议的研究中，DENV-2 和 DENV-4 之间的竞争模式将在蚊子体内进行测试。 随后，我们将使用相同的方法来测量一组森林和地方性 DENV-2 体内分离株的竞争性抑制。 竞争性抑制将被测量为特定分离株与常见 DENV-4 竞争者共同感染时与单独感染时所达到的滴度。 将比较森林和地方性分离株的相对竞争性抑制。 如果森林分离株与其他地方性分离株相比，对地方性 DENV-4 的竞争能力较差，这将支持以下假设：竞争可能有助于将森林化 DENV 排除在地方性流行周期之外。