Genomic epidemiology of Plasmodium falciparum and Anopheles vectors in the context of malaria control on the Bijagós Archipelago of Guinea Bissau

疟疾是一种由原生动物疟原虫引起的疾病，每年造成40多万人死亡，其中大多数死亡发生在5岁以下儿童中。世界卫生组织致力于帮助到2030年将疟疾死亡率降低90%。尽管高覆盖率使用长效杀虫剂处理的蚊帐、室内滞留喷洒和青蒿素类联合疗法成功地降低了死亡率，但这些工具本身显然不足以消除疟疾。需要新的工具来处理人类和病媒感染库。联合ACT的大规模给药（MDA）已被提议作为减少人类感染库的一种策略。联合使用有效的ACT和伊维菌素（IVM）作为MDA，应同时解决无症状的人类宿主和可能阻断传播的另一种媒介控制方法。该博士项目嵌套在几内亚比绍比加戈斯群岛目前资助的集群（岛屿）随机安慰剂对照试验中。该试验将评估丙二醛与辅助IVM在联合青蒿素-哌喹（DP）治疗之外的额外影响。博士项目将利用试验设计和岛屿地理位置偏远的优势，调查MDA干预前恶性疟原虫的种群结构和耐药性概况，MDA对恶性疟原虫传播的影响，以及在MDA期间和之后使用新的分子和建模技术表征和跟踪残留的恶性疟原虫变异。将利用分子和生物信息学技术，利用野外采集的干血点，在基线上确定寄生虫传播、种群结构和对已知抗疟疾药物的耐药性。恶性疟原虫全基因组测序将与研究期间基于现场的人口流动元数据相结合，用于在MDA前后描述和跟踪恶性疟原虫变异。利用MDA后采集的干血点进行干预后，将确定寄生虫传播、种群结构和耐药性的变化。预计这项研究将支持制定针对疟疾暴发、消除运动和流行病学监测的创新方案方法。本研究将进一步调查传播恶性疟原虫的疟蚊媒介对杀虫剂的抗性。在这些岛屿上控制疟疾的主要方法是使用浸有杀虫剂的长效驱虫蚊帐。杀虫剂耐药性在全球广泛存在，并威胁到杀虫剂和其他病媒控制干预措施的使用。对群岛上疟疾病媒的杀虫剂抗性状况了解甚少。该研究项目将使用表型分析和多重扩增子方法来研究这一问题，这是一种新的高通量基因组技术。该项目需要广泛的定量和跨学科技能，符合MRC的战略技能优先事项。定量技能要求包括处理大型数据集，生物信息学分析和统计分析，这将包括优秀的R统计软件包和bash和python技能的开发。在寄生虫基因组序列技术和基因组流行病学方面需要进一步的技术技能。还将发展跨学科技能和知识，包括与基因组流行病学、临床试验、抗疟疾耐药性、公共卫生干预和疾病控制方法中的批判性思维有关的技能和知识。此外，该项目涉及发展葡萄牙语和葡萄牙Kriol语言技能，以完成在Bijagós群岛的实地工作。

Malaria is a disease caused by the protozoan organism Plasmodium, which kills over 400,000 people annually, with the majority of deaths occurring in children under 5 years old. The World Health Organisation is committed to help reduce malaria mortality by 90% by 2030. Despite the high coverage use of long-lasting insecticide treated bed nets (LLINs), indoor residual spraying (IRS) and artemisinin-based combination therapy (ACT) successfully reducing mortality, these tools are clearly insufficient on their own to eliminate malaria. New tools are required to address both the human and vector reservoirs of infection. Mass drug administration (MDA) with ACT has been proposed as a strategy to reduce the human reservoir of infection. The combination of an efficacious ACT and the mosquitocidal agent ivermectin (IVM) as MDA should address both the asymptomatic human reservoirs and an additional vector control approach that may interrupt transmission.This PhD project is nested within a currently funded cluster (island) randomised placebo-controlled trial on the Bijagos Archipelago of Guinea-Bissau. The trial will evaluate the added impact of MDA with adjunctive IVM in addition to the ACT dihydroartemisinin-piperaquine (DP). The PhD project will take advantage of the trial design and geographical remoteness of the islands to investigate the population structure and drug resistance profile of P. falciparum before the MDA intervention, the impact of MDA on P. falciparum transmission and the characterisation and tracking of residual P. falciparum variants during and post-MDA using novel molecular and modelling techniques. Molecular and bioinformatics techniques will be used to determine parasite transmission, population structure and resistance profile to known anti-malarial drugs at baseline using field collected dry blood spots. P. falciparum whole genome sequencing will be used to characterise and track P. falciparum variants before and after MDA in combination with field-based metadata on human population movement during the study. The change in parasite transmission, population structure and resistance profile will be determined following intervention using dry blood spots collected after the MDA. This research is expected to support the development of innovative programmatic approaches to malaria outbreaks, elimination campaigns and epidemiological surveillance.This research will further investigate insecticide resistance in the Anopheles mosquito vectors which transmit P. falciparum. The mainstay of malaria control on the islands is the use of Long-Lasting Insecticidal Nets, which are impregnated with insecticides. Insecticide resistance is widespread globally and threatens the use of LLINs and other vector control interventions. The insecticide resistance status of malaria vectors on the archipelago is poorly understood. This research project will investigate this using both phenotypic assays and multiplex amplicon approaches, which are a novel high-throughput genomic technique.This project requires a wide range of quantitative and interdisciplinary skills which fit within the MRC's strategic skills priorities. Quantitative skills required include working with large datasets, bioinformatic analytics and statistical analysis, which will include excellence in R statistical package and the development of skills in bash and python. Further technological skills in parasite genome sequence technology and genomic epidemiology will be required. Interdisciplinary skills and knowledge will also be developed, including those related to genomic epidemiology, clinical trials, antimalarial resistance, public health interventions and critical thinking in disease control methods. Furthermore, this project involves developing Portuguese and Portuguese Kriol language skills in order to complete fieldwork in the Bijagós archipelago.