Population genomics and new tools for the endgame of onchocerciasis elimination in Africa

摘要 伊维菌素(CDTI)在美洲和非洲的社区定向治疗的成功导致了 消除引起盘尾丝虫病的丝状线虫感染的目标 到2025年，非洲80%的地方病国家。这一雄心勃勃的目标不仅取决于维持药品覆盖 而且还在高流行区维持药物敏感性长达25年的治疗期， 预防CDTI后因来自尚未消灭的地区的寄生虫再次入侵而复发 已经实现了。成功和可持续消除的这两个要求要求制定 能够常规监测伊维菌素敏感性和模拟寄生虫迁移的新工具 几个空间和时间尺度，以便可以客观地估计CDTI后复发的风险。 我们建议扩展我们现有的关于伊维菌素反应的遗传相关性的数据，以开发一个 预测这种反应的遗传标记作为伊维菌素简单基因分型监测工具的基础 功效，并扩展我们现有的关于旋毛虫种群结构的数据，以将数学上的 盘尾丝虫病模型(EpiOncho)，以便可以定量地估计复发风险。我们会带着 伊维菌素所致&gt；300成虫的Out基因测序及遗传关联分析 反应是已知的，然后测试得到的一组遗传标记准确预测的能力 伊维菌素治疗之前未特指的其他病灶后皮肤的复发率 在非洲其他地方。类似地，我们将对地理上不同的大型生物进行基因分型 从整个非洲挑选微丝虫病和感染性幼虫，以开发和测试一组标记， 定义寄生虫传播区的边界，并可用于将寄生虫分配给 起源。这些数据将被用来对EpiOncho的“补丁模型”版本进行参数化。预期的结果 将促进开发急需的工具，以(一)监测伊维菌素的疗效(二)估计术后的风险 治疗复发率和(3)有助于成功消除盘尾丝虫病。

SUMMARY The success of Community Directed Treatment with Ivermectin (CDTI) in the Americas and Africa has led to a target of eliminating infection with Onchocerca volvulus, the filarial nematode that causes onchocerciasis, in 80% of endemic African countries by 2025. This ambitious goal depends on sustaining not only drug coverage but also sustaining drug sensitivity for treatment periods as long as 25 years in hyperendemic foci, and also on preventing post-CDTI recrudescence due to reinvasion of parasites from regions where elimination has not been achieved. These two requirements for successful and sustainable elimination require the development of new tools capable of routine monitoring of ivermectin susceptibility and of modelling parasite migration over several spatial and temporal scales so that the risk of post-CDTI recrudescence can be estimated objectively. We propose to extend our existing data on genetic associations for ivermectin response to develop a panel of genetic markers predictive of that response as the basis for a simple genotyping surveillance tool for ivermectin efficacy, and to extend our existing data on O. volvulus population structure to parameterize a mathematical model of onchocerciasis (EpiOncho) so that recrudescence risk can be estimated quantitatively. We will carry out genotype-by-sequencing and genetic association analysis on >300 adult female worms whose ivermectin response is known then test the ability of the resulting panel of genetic markers to accurately predict repopulation rates in the skin following ivermectin treatment in additional, previously uncharacterized foci elsewhere in Africa. Similarly, we will carry out genotyping-by-sequencing of a large, geographically diverse selection of microfilariae and infective larvae from throughout Africa to develop and test a panel of markers that define the boundaries of parasite transmission zones and can be used to assign parasites to a population of origin. These data will be used to parameterize a “patch model” version of EpiOncho. The expected outcome will promote development of much needed tools to (i) monitor ivermectin efficacy (ii) estimate risk of post- treatment recrudescence and (iii) facilitate successful elimination of onchocerciasis.