Trajectory of Vector-adaptive Chikungunya Virus Evolution

 描述(申请人提供)：基孔肯雅(CHIKV)是一种重新出现的蚊媒病毒，起源于非洲地方病周期，但周期性地启动城市周期，涉及人类放大宿主和城市媒介蚊子埃及伊蚊和最近的白纹伊蚊。自2004年以来，通过受感染的旅行者传播的CHIKV已将CHIKV带入亚洲、欧洲、大洋洲和美洲，导致数百万例严重、虚弱、通常是慢性关节痛。印度洋血统(IOL)最近出现的菌株的一个特征是白纹伊蚊包膜糖蛋白中一系列适应白纹伊蚊的替换的进化。这些突变提高了该物种在印度洋盆地和亚洲的传播效率。集中在E1蛋白融合环附近(残基226)和E2酸敏感区域的IOL替换模式表明，通过改变病毒尖峰构象变化的pH阈值，影响了CHIKV进入蚊子细胞。这一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白纹伊蚊更有效的传播。然而，这些“第二步”的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，媒介特异性适应亚洲血统的历史从未被探索过。因此，目前在美洲的亚洲CHIKV血统的媒介适应轨迹及其对传播和地方性的影响仍然是不可预测的，尽管存在重大的公共卫生影响。认识上的关键差距包括：1)亚洲血统已经/将(进一步)适应美洲埃及伊蚊的传播，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替换是否会增加亚洲株对白纹伊蚊或埃及伊蚊的传染性？以及；3)随着传播在美洲的继续，我们能否预测更多的媒介适应性CHIKV进化？我们通过4个具体目标来解决这些关键问题：1.描述自1958年以来亚洲CHIKV谱系的媒介适应性进化历史，并利用这些发现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，以确定更多的媒介适应性进化。3.确定“第二步”载体适应性的E2替换对亚洲脊椎中白纹伊蚊或埃及伊蚊的感染性的影响。4.使用前瞻性的方法，对来自美洲的实验操纵的CHIKV毒株进行深度测序，以确定可能影响西半球媒介使用的潜在适应性突变。这一结果不仅将改善对即将和未来的CHIKV疫情的预测，还将为直接影响公共卫生的监测和病媒控制工作提供信息。

 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.