Epidemiology and determinants of emerging artemisinin-resistant malaria in Ethiopia

项目摘要 对一线青蒿素联合疗法具有抗药性的恶性疟原虫菌株威胁着 非洲的疟疾控制和消除工作，世界上95%的疟疾病例和死亡发生在非洲。 青蒿素耐药性是由pfkelch 13（K13）基因突变介导的，这些突变最近才影响到 本地区关于K13突变现已在非洲得到证实，包括出现和扩展 候选青蒿素耐药K13 R622 I突变在非洲之角（HoA）。越来越多的报告来自 我们和其他人HoA还表明，通过广泛使用的抗病毒药物 由于富含组氨酸的蛋白2/3（pfhrp 2/3）基因的缺失， 在整个地区。药物和诊断耐药突变的双重出现威胁着一线检测- 并可能对疟疾控制产生深远影响。更好地了解 R622 I寄生虫感染的决定因素，为临床实践和政策决策提供信息。在 与埃塞俄比亚公共卫生研究所合作，该研究所是埃塞俄比亚联邦卫生部的技术部门， 健康，和领先的学术合作伙伴，我们将进行调查的人提出的卫生设施， 埃塞俄比亚的恶性疟疾，并实现以下目标。在目标1中，我们将阐明 抗青蒿素恶性疟原虫感染，包括是否存在pfhrp 2/3 删除会影响风险。我们将开发一种临床风险工具来帮助预测谁可能被青蒿素感染- 抗性寄生虫这一工具可用于有针对性地实施抗疟治疗方案 旨在克服耐药性并防止其传播，例如采用两种伙伴药物的三重ACT 以及青蒿素衍生物。在目标2中，我们将确定K13 R622 I对耐药性的影响 以及PFHRP 2/3缺失和完整寄生虫中的寄生虫适合度。在目标3中，我们将开发一个预测模型， 青蒿素耐药性在HoA内外的未来传播，首先关注数据/模型的开发 的人和寄生虫迁移，然后整合在体内数据从目标1和体外数据从目标2。 总之，这些目标将提高我们对流行病学和新兴青蒿素驱动因素的理解 并产生可用于疟疾项目识别、预测和应对的工具 非洲新出现的耐药菌株。

PROJECT SUMMARY Plasmodium falciparum strains with resistance to first-line artemisinin-combination therapies (ACTs) threaten malaria control and elimination efforts across Africa, where 95% of the world's malaria cases and deaths occur. Artemisinin resistance is mediated by mutations in the pfkelch13 (K13) gene that have only recently impacted the region. Concerning K13 mutations have now been confirmed in Africa, including emergence and expansion of the candidate artemisinin-resistance K13 R622I mutation in the Horn of Africa (HoA). Increasing reports from the HoA by us and others also indicate that “diagnosis resistant” strains that escape detection by widely used rapid diagnostic tests due to deletions of the histidine-rich protein 2/3 (pfhrp2/3) genes are now established across the region. The dual emergence of drug and diagnostic resistance mutations threatens frontline test- and-treat strategies and may have profound impacts on malaria control. Improved understanding of the determinants of infection by R622I parasites is needed to inform clinical practice and policy decisions. In collaboration with the Ethiopian Public Health Institute, the technical arm of the Ethiopia Federal Ministry of Health, and leading academic partners, we will conduct surveys of people presenting to health facilities with falciparum malaria across Ethiopia and achieve the following Aims. In Aim 1, we will elucidate risk factors for infection by artemisinin-resistant P. falciparum, including whether the presence or absence of pfhrp2/3 deletions impacts risk. We will develop a clinical risk tool to help predict who may be infected by an artemisinin- resistant parasite. Such a tool could be used for targeted implementation of antimalarial treatment options designed to overcome resistance and prevent its spread, such as triple ACT that employs two partner drugs alongside an artemisinin derivative. In Aim 2, we will determine the impact of K13 R622I on drug resistance and parasite fitness in pfhrp2/3-deleted and intact parasites. In Aim 3, we will develop a predictive model of the future spread of artemisinin resistance within and out of the HoA, focusing first on development of data/models of human and parasite migration and then integrating in vivo data from Aim 1 and in vitro data from Aim 2. Together, these Aims will improve our understanding of the epidemiology and drivers of emerging artemisinin resistance in the HoA and produce tools that can be used by malaria programs to identify, predict, and respond to emerging drug-resistant strains in Africa.