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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 登革病毒（黄病毒属）是节肢动物传播病毒中对公共卫生最严重的威胁，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居住区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物种和非人类灵长类之间循环。 地方性病毒和森林病毒显示出高度的序列同源性，但森林病毒不会在人类中引起暴发。我们最初的假设来解释这一明显的悖论是，一个“适应性屏障”防止出现的森林登革热病毒，或更具体地说，森林登革热病毒复制差，无论是在人类或在peridomestic伊蚊物种。然而，在与INBRE导师Scott Weaver（UTMB）及其实验室成员的合作中，我们已经证明不存在这种适应性障碍，因为DENV血清型2（DENV-2）的森林和地方毒株对人类病毒复制模型（Vasilakis et al. 2007，Vaslakis et al. submitted，Vasilakis et al. in preparation）和Ae.埃及伊蚊，地方性登革热的主要媒介（汉利等人，准备中）。 森林登革热对森林循环的限制的另一种解释是，与登革病毒地方毒株的竞争阻止了森林毒株的出现。因此，我们目前的研究重点是表征地方性和森林性DENV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媒介中，但更可能发生在感染持续终生的媒介中。我们最近已经证明，当DENV-2和DENV-4的混合感染同时（共感染）或以第一和第二血清型的引入之间的指定间隔（重复感染）引入培养的蚊子细胞时，每种血清型的复制降低，感染的总体生产率也降低（Pepin等，出版中，Pepin和汉利，准备中）。 此外，抑制是最强的菌株感染第二次在重叠感染治疗。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分离株在体内的竞争性抑制。 竞争性抑制将被测量为当特定分离株与常见的DENV-4竞争者共感染时与当其单独感染时相比所实现的滴度。 将比较森林化和地方性分离株的相对竞争抑制。 如果与其他地方性分离株相比，森林化分离株对地方性DENV-4的竞争力较差，则这将支持竞争可能有助于将森林化DENV排除在地方性循环之外的假设。