Epidemiology and determinants of emerging artemisinin-resistant malaria in Ethiopia

项目总结 对青蒿素联合疗法(ACTS)一线耐药的恶性疟原虫株构成威胁 全世界95%的疟疾病例和死亡都发生在非洲各地的疟疾控制和消除工作中。 青蒿素耐药性是由PfKelch13(K13)基因突变介导的，这些突变是最近才产生影响的 该地区。关于K13的突变现已在非洲得到证实，包括出现和扩大 非洲之角(HoA)候选青蒿素抗性K13 R622I突变。增加来自以下方面的报道 我们和其他人的HoA还表明，逃脱广泛使用的检测的“诊断耐药”菌株 富含组氨酸蛋白2/3(pfhrp2/3)基因缺失引起的快速诊断试验现已建立 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- 和治疗战略，并可能对疟疾控制产生深远影响。更好地理解 R622I寄生虫感染的决定因素需要为临床实践和政策决策提供信息。在……里面 与埃塞俄比亚联邦卫生部的技术部门埃塞俄比亚公共卫生研究所合作 健康，和领先的学术合作伙伴，我们将对向卫生机构提出建议的人进行调查 在埃塞俄比亚全境传播恶性疟疾，并实现以下目标。在目标1中，我们将阐明以下风险因素 感染耐青蒿素恶性疟原虫，包括是否存在pfhrp2/3 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感染青蒿素- 具有抗药性的寄生虫。这种工具可用于有针对性地实施抗疟疾治疗方案。 旨在克服耐药性并防止其传播，例如使用两种伙伴药物的三联疗法 旁边还有一种青蒿素衍生品。在目标2中，我们将确定K13 R622I对耐药性的影响 以及在pfhrp2/3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，首先侧重于数据/模型的开发 然后整合来自AIM 1的体内数据和来自AIM 2的体外数据。 综合起来，这些目标将提高我们对新出现的青蒿素的流行病学和驱动因素的理解 在HoA中产生耐药性，并生产可供疟疾项目使用的工具来识别、预测和应对 对非洲新出现的耐药菌株的影响。

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.