Trajectory of Vector-adaptive Chikungunya Virus Evolution

载体适应性基孔肯雅病毒的进化轨迹

基本信息

批准号：
9009006
负责人：
Scott C Weaver
金额：
$ 46.92万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9009006
关键词：
Acids Address Aedes Affect Africa African Americas Arboviruses Arthralgia Asia Asian Indian Asians Blood Circulation Caribbean region Cells Central America Chikungunya virus Chronic Culicidae Dengue Virus Dependence Disease Outbreaks Economics Epidemic Europe Evolution Future Genetic Glycoproteins Goals Health Human Human papillomavirus 16 E1 protein Indian Ocean Infection Intervention Latin America Mediating Mutation Nature North America Oceania Pattern Persons Phenotype Phylogenetic Analysis Population Proteins Public Health RNA Viruses Recording of previous events Reunion Island Risk Role Series South African South America Southeastern Asia Testing Therapeutic Time Vaccines Vertebral column Viral Virus Virus Diseases chikungunya deep sequencing enzootic fitness genetic approach improved nonhuman primate prospective public health relevance response transmission process vector vector control vector mosquito viral transmission

项目摘要

DESCRIPTION (provided by applicant): Chikungunya (CHIKV) is a reemerging mosquito-borne virus that originates in an enzootic African cycle but periodically initiates an urban cycle involving human amplification hosts and the urban vector mosquitoes, Aedes aegypti and recently, A. albopictus. Since 2004, Spread via infected travelers has introduced CHIKV into Asia, Europe, Oceania and the Americas with millions of cases of severe, debilitating, often chronic arthralgia. A hallmark of recently emerged strains in the Indian Ocean Lineage (IOL) has been the evolution of a series of A. albopictus-adaptive substitutions in the envelope glycoproteins. These mutations increase transmission efficiency by this species in the Indian Ocean basin and Asia. A pattern of IOL substitutions focused near the fusion loop of the E1 protein (residue 226) and in the acid sensitive region of E2 suggests an effect on CHIKV entry into mosquito cells by altering the pH threshold for conformational changes in the viral spikes. This pattern allowed us to predict additional adaptive E2 substitutions, never detected in nature, and to show that a combination of these substitutions will soon result in even more efficient transmission by A. albopictus. However, the dependence of these "second-step" E2 mutations on E1-226, and their phenotypes in the genetic background of the Asian lineage recently introduced into the Americas, remain unknown. Furthermore, the history of vector-specific adaptation of the Asian Lineage has never been explored. Therefore, the vector-adaptive trajectory of the Asian CHIKV lineage now in the Americas and its effect on spread and endemicity remains unpredictable despite major public health implications. Critical gaps in understanding include: 1) Has/will the Asian lineage (further) adapt for A. aegypti transmission in the Americas, and will such adaptation affect transmission by A. albopictus?; 2) Can A. albopictus-adaptive E2 substitutions increase Asian strain infectivity for A. albopictus or A. aegypti? and; 3) Can we predict additional vector-adaptive CHIKV evolution as spread continues in the Americas? We address these critical questions using 4 specific aims: 1. Characterize the vector-adaptive evolutionary history of the Asian CHIKV lineage since 1958, and use the findings to predict the future evolutionary trajectory of this strain in the Americas. . Follow the evolution of both Asian and IOL CHIKV strains in Asia and the Americas to identify additional vector-adaptive evolution. 3. Determine the effects of "second-step" vector-adaptive E2 substitutions on infectivity for A. albopictus or A. aegypti in the Asian backbone. 4. Use a prospective approach with deep sequencing of experimentally manipulated CHIKV strains from the Americas to identify potential adaptive mutations that could affect vector usage in the Western Hemisphere. The results will not only improve prediction of imminent and future CHIKV epidemics, but also will inform surveillance and vector control efforts to directly impact public health.

描述（由申请人提供）：基孔肯雅热（CHIKV）是一种重新出现的蚊媒病毒，起源于非洲地方性动物循环，但定期启动涉及人类扩增宿主和城市媒介蚊子、埃及伊蚊和最近的白纹伊蚊的城市循环。自 2004 年以来，CHIKV 通过受感染的旅行者传播，已进入亚洲、欧洲、大洋洲和美洲，造成数百万重症、印度洋谱系 (IOL) 最近出现的菌株的一个标志是包膜糖蛋白中一系列白纹伊蚊适应性取代，这些突变提高了该物种在印度的传播效率。大洋盆地和亚洲。IOL 替换的模式集中在 E1 蛋白的融合环（残基 226）和 E2 的酸敏感区域，表明对 CHIKV 进入有影响。通过改变病毒刺突构象变化的 pH 阈值进入蚊子细胞，这种模式使我们能够预测在自然界中从未检测到的额外的适应性 E2 替换，并表明这些替换的组合将很快导致更有效的传播。然而，这些“第二步”E2 突变对 E1-226 的依赖，以及它们在最近引入美洲的亚洲谱系遗传背景中的表型，仍然未知。适应因此，亚洲 CHIKV 谱系目前在美洲的媒介适应性轨迹及其对传播和流行的影响仍然不可预测，尽管对公共卫生的重大影响包括：1) 是否存在/。亚洲谱系是否会（进一步）适应埃及伊蚊在美洲的传播，这种适应是否会影响白纹伊蚊的传播？；2) 白纹伊蚊适应性 E2 替代品能否替代增加白纹伊蚊或埃及伊蚊的亚洲毒株感染性 3) 随着美洲的传播，我们能否预测更多的载体适应性 CHIKV 进化？我们通过 4 个具体目标来解决这些关键问题： 1. 描述载体适应性的特征自 1958 年以来亚洲 CHIKV 谱系的进化历史，并利用这些发现来预测该病毒株在美洲的未来进化轨迹。亚洲和美洲的 CHIKV 菌株，以识别其他载体适应性进化 3. 确定“第二步”载体适应性 E2 替换对亚洲骨干中白纹伊蚊或埃及伊蚊感染性的影响。一种前瞻性方法，对来自美洲的实验操纵的 CHIKV 毒株进行深度测序，以识别可能在西半球使用载体的潜在适应性突变。结果不仅会改善预测。迫在眉睫和未来的 CHIKV 流行病，而且还将为监测和病媒控制工作提供信息，以直接影响公共卫生。