Trajectory of Vector-adaptive Chikungunya Virus Evolution

载体适应性基孔肯雅病毒的进化轨迹

• 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
• 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

 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（由适用提供）：Chikungunya（Chikv）是一种重新出现的蚊子传播病毒，起源于非洲循环，但会定期启动涉及人类扩增宿主的城市周期和城市媒介蚊子，埃德斯·埃及和最近的A. albopictus。自2004年以来，通过受感染的旅行者的传播将Chikv引入了亚洲，欧洲，大洋洲和美洲，数以百万计的严重，令人衰弱，经常经常慢性直立属的案例。最近在印度海洋谱系（IOL）中出现的菌株的标志是信封糖蛋白中一系列白化曲霉自适应替代的进化。这些突变提高了印度洋盆地和亚洲中该物种的传播效率。 IOL取代的模式集中在E1蛋白的融合环（残基226）和E2的酸敏感区域附近，这表明对Chikv进入蚊子细胞的影响通过改变病毒尖峰构象变化的pH阈值来影响。这种模式使我们能够预测自然界从未检测到的其他自适应E2取代，并表明这些取代的组合很快将导致白化曲霉的效率更高。但是，这些“二阶” E2突变对E1-226的依赖性，以及它们在最近引入美洲的亚洲血统的遗传背景中的表型仍然未知。此外，从未探索过亚洲血统的特定于矢量适应的历史。因此，目前在美洲的亚洲志夫血统的向量自适应轨迹及其对传播和内在的影响仍然是不可预测的主要公共卫生影响。理解中的关键差距包括：1）具有/将有亚洲血统（进一步）适应美洲的A. eegypti传播，并且这种适应会影响A. albopitctus的传播？ 2）白曲霉的自适应E2取代可以增加亚洲白曲霉或A. aegypti的亚洲菌株感染吗？和; 3）我们可以预测随着美洲蔓延的差异而继续进行额外的媒介自适应chikv进化吗？我们使用4个特定目的解决了这些关键问题：1。表征自1958年以来亚洲Chikv血统的向量自适应进化史，并利用这些发现来预测美洲这种菌株的未来进化轨迹。 。遵循亚洲和美洲的亚洲和IOL CHIKV菌株的演变，以鉴定额外的媒介自适应进化。 3。确定“二阶”载体自适应E2取代对亚洲主链中白化曲霉或A. aegypti感染的影响。 4.使用一种前瞻性方法对来自美洲的实验操纵CHIKV菌株进行深度测序，以识别可能影响西半球矢量使用的潜在适应性突变。结果不仅会改善对即将来临和未来的Chikv流行病的预测，而且还将为监视和媒介控制工作提供信息，以直接影响公共卫生。