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

总结 伊维菌素社区定向治疗（CDTI）在美洲和非洲的成功， 消除盘尾丝虫（引起盘尾丝虫病的丝虫线虫）感染的目标， 到2025年，80%的非洲流行国家。这一雄心勃勃的目标不仅取决于维持药物覆盖率， 而且在高流行病疫源地的治疗期长达25年， 预防CDTI后由于来自尚未消除的地区的寄生虫再次入侵而复发 办妥了一批多年想成功和可持续消除的这两个要求需要制定 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，使CDTI后复发的风险可以客观地估计。 我们建议扩展我们现有的关于伊维菌素反应遗传关联的数据，以开发一个 预测该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 有效性，并扩展我们现有的数据O。肠扭转人口结构参数化的数学 盘尾丝虫病（EpiOncho）模型，以便可以定量估计复发风险。创新实施 对300多只伊维菌素致敏的成年雌蠕虫进行基因型测序和遗传关联分析 反应是已知的，然后测试所得到的遗传标记小组的能力，以准确地预测 伊维菌素治疗后，在其他先前未表征的病灶中的皮肤再增殖率 在非洲的其他地方。同样，我们将对一个大的，地理上多样化的， 选择来自整个非洲的微丝蚴和感染性幼虫，以开发和测试一组标记物， 定义寄生虫传播区的边界，并可用于将寄生虫分配给 起源这些数据将用于参数化EpiOncho的“补丁模型”版本。预期结果 将促进开发急需的工具，以（i）监测伊维菌素的疗效（ii）估计 治疗复发和（iii）促进盘尾丝虫病的成功消除。

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.