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，每年导致40多万人死亡，其中大部分死亡发生在5岁以下的儿童中。世界卫生组织承诺到2030年帮助将疟疾死亡率降低90%。尽管长效驱虫蚊帐(LLIN)、室内残留喷洒(IRS)和以青蒿素为基础的综合疗法(ACT)的高覆盖率成功降低了死亡率，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媒介感染宿主问题。大众给药(MDA)联合ACT已被提出为减少人类感染宿主的一种策略。有效的ACT和灭蚊剂伊维菌素(IVM)作为丙二醛的组合，应该既可以解决无症状的人类宿主，也可以解决可能中断传播的另一种媒介控制方法。该博士项目嵌套在目前资助的一项在几内亚比绍比亚戈斯群岛进行的随机(岛屿)安慰剂对照试验。该试验将评估在ACT双氢青蒿素哌喹(DP)的基础上加用静脉注射丙二醛(MDA)的额外影响。该博士项目将利用这些岛屿的试验设计和地理偏远的优势，利用新的分子和建模技术，调查丙二醛干预之前恶性疟原虫的种群结构和抗药性特征，丙二醛对恶性疟原虫传播的影响，以及在丙二醛感染期间和之后残留的恶性疟原虫变异的特征和跟踪。分子和生物信息学技术将被用来确定寄生虫的传播，种群结构和对已知抗疟疾药物的耐药性，在基线上使用现场采集的干血点。在这项研究中，恶性疟原虫全基因组测序将被用来描述和跟踪在丙二醛之前和之后的恶性疟原虫变异，并结合基于现场的人口迁移的元数据。寄生虫传播、种群结构和抗药性的变化将通过使用丙二醛疫情后收集的干血斑点进行干预后确定。这项研究预计将支持疟疾暴发、消灭运动和流行病学监测的创新规划方法的发展。这项研究将进一步调查传播恶性疟原虫的按蚊媒介的抗药性。在这些岛屿上控制疟疾的主要手段是使用长效杀虫蚊帐，这种蚊帐浸透了杀虫剂。杀虫剂抗药性在全球普遍存在，并威胁到LLINs和其他媒介控制干预措施的使用。群岛上疟疾病媒的抗药性状况知之甚少。这项研究项目将使用表型分析和多重扩增子方法来研究这一点，这是一种新的高通量基因组技术。这个项目需要广泛的定量和跨学科技能，这些技能符合MRC的战略技能优先事项。所需的量化技能包括处理大数据集、生物信息分析和统计分析，其中将包括在R统计包方面的卓越表现以及在bash和蟒蛇方面的技能发展。将需要在寄生虫基因组序列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、抗疟疾耐药性、公共卫生干预和疾病控制方法的批判性思维有关的技能和知识。此外，该项目还涉及培养葡萄牙语和葡萄牙语克里奥尔语技能，以便在比亚戈·S群岛完成实地工作。

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.