Trajectory of Vector-adaptive Chikungunya Virus Evolution

 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，起源于非洲地方病循环，但周期性地启动城市循环，涉及人类扩增宿主和城市媒介蚊子埃及伊蚊，以及最近的埃及伊蚊。白纹伊蚊自2004年以来，通过受感染的旅行者传播的CHIKV已将CHIKV引入亚洲，欧洲，大洋洲和美洲，数百万例严重，衰弱，通常是慢性关节痛。最近在印度洋谱系（IOL）中出现的菌株的一个标志是一系列A。在包膜糖蛋白中的白纹伊蚊适应性取代。这些突变增加了该物种在印度洋盆地和亚洲的传播效率。IOL取代的模式集中在E1蛋白的融合环（残基226）附近和E2的酸敏感区中，表明通过改变病毒刺突中构象变化的pH阈值对CHIKV进入蚊子细胞的影响。这种模式使我们能够预测额外的适应性E2取代，在自然界中从未检测到，并表明这些取代的组合将很快导致A更有效的传播。白纹伊蚊然而，这些“第二步”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遗传背景中的表型，仍然是未知的。此外，亚洲血统的媒介特异性适应的历史从未被探索过。因此，尽管存在重大的公共卫生影响，但目前在美洲的亚洲CHIKV谱系的媒介适应性轨迹及其对传播和地方性的影响仍然不可预测。理解上的关键差距包括：1）亚洲血统（进一步）适应A。埃及伊蚊在美洲的传播，这种适应是否会影响A. albopictus？; 2)能A.白纹伊蚊适应性E2置换增加了亚洲菌株对A. albopictus或A.埃及？和; 3）我们能否预测更多的载体适应CHIKV的演变，传播继续在美洲？我们使用4个具体目标来解决这些关键问题：1。描述自1958年以来亚洲CHIKV谱系的载体适应性进化历史，并利用研究结果预测该毒株在美洲的未来进化轨迹。.跟踪亚洲和美洲的亚洲和IOL CHIKV毒株的进化，以确定其他载体适应性进化。3.确定“第二步”载体适应性E2置换对A. albopictus或A.埃及人在亚洲的脊梁。4.使用前瞻性方法对来自美洲的实验操作CHIKV毒株进行深度测序，以确定可能影响西半球载体使用的潜在适应性突变。这些结果不仅将改善对即将发生和未来的CHIKV流行的预测，而且还将为监测和病媒控制工作提供信息，直接影响公共卫生。

 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.