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岁以下的儿童中。世界卫生组织致力于到2030年将疟疾死亡率降低90%。尽管使用长效驱虫蚊帐、室内滞留喷洒和青蒿素类复方疗法的覆盖率很高，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。需要新的工具来解决人类和病媒的感染宿主。大规模药物管理（MDA）与ACT已被提出作为一种战略，以减少人类水库的感染。一个有效的ACT和灭蚊剂伊维菌素（伊维菌素）MDA的组合应解决无症状的人类水库和一个额外的载体控制方法，可能会中断transmission.This博士项目嵌套在一个目前资助的集群（岛）随机安慰剂对照试验在几内亚比绍的比热戈斯群岛。该试验将评价在ACT双氢青蒿素-哌喹（DP）基础上，MDA与连续性IVM的额外影响。该博士项目将利用试验设计和岛屿的地理偏远性，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，以及使用新型分子和建模技术在MDA期间和之后表征和跟踪残留的恶性疟原虫变体。分子和生物信息学技术将用于确定寄生虫的传播，人口结构和耐药性的已知抗疟疾药物在基线使用现场收集的干血点。恶性疟原虫全基因组测序将用于在MDA之前和之后结合研究期间人口流动的基于实地的元数据来鉴定和跟踪恶性疟原虫变体。将使用MDA后收集的干血斑确定干预后寄生虫传播、种群结构和抗性概况的变化。这项研究将有助于制定应对疟疾暴发、消灭疟疾运动和流行病监测的创新方案，并将进一步调查传播恶性疟原虫的按蚊媒介对杀虫剂的抗药性。这些岛屿控制疟疾的主要手段是使用长效驱虫蚊帐，蚊帐中浸有杀虫剂。杀虫剂抗药性在全球范围内普遍存在，威胁到长效驱虫蚊帐和其他病媒控制干预措施的使用。人们对群岛上疟疾病媒的杀虫剂抗药性状况知之甚少。本研究项目将使用表型分析和多重扩增子方法进行研究，这是一种新型的高通量基因组技术。本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。所需的定量技能包括使用大型数据集，生物信息学分析和统计分析，其中包括R统计软件包的卓越表现以及bash和python技能的发展。将需要寄生虫基因组测序技术和基因组流行病学方面的进一步技术技能。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、抗疟抗药性、公共卫生干预措施和疾病控制方法中的批判性思维有关的技能和知识。此外，该项目还涉及发展葡萄牙语和葡萄牙语Kriol语言技能，以完成在比热戈斯群岛的实地工作。

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.