Plasmodium falciparum anti-malarial drug resistance in The Gambia:Identification of potential genetic markers by retrospective whole genome approaches

由感染恶性疟原虫引起的疟疾仍然是一个重要的全球健康问题。需要更多的信息来继续开发控制这种疾病的新方法，这种疾病主要感染撒哈拉以南非洲的贫穷流行国家。其中一些信息包括不同类型寄生虫之间的遗传差异，特别是那些对目前用于治疗的药物不起作用的寄生虫。疟疾已经对以前可获得的廉价药物，如氯喹和范西达产生了抗药性。由于这种强大的能力来开发新的方法来逃避药物和持续传播感染并在其他人中引起疾病，现在需要使用含有复方青蒿素(ART)的新药物组合来治疗感染。这些新药组合(ACT)更昂贵，是撒哈拉以南非洲疟疾感染的唯一最有效的治疗方法。然而，有迹象表明，用这些新的药物组合治疗东南亚的一些疟疾感染并不像预期的那样有效，这表明寄生虫可能已经在开发新的机制来抵抗这些药物组合的效果。如果这种令人震惊的事态发展继续下去并蔓延到非洲，将对减轻非洲大陆疟疾负担的努力造成重大打击，非洲大陆承担着90%的疟疾负担。为了让科学界为这种可能的情况做好准备，重要的是开始寻找使这些抵抗药物行动的寄生虫在受影响的撒哈拉以南阿里卡人口中发展和传播的因素。其中一些因素包括一些寄生虫对通常会杀死它们的药物浓度的耐受能力。在了解造成抗药性条件的寄生虫中的复杂过程方面，挑战在于需要从使用这些药物一段时间的人群中获得大量数据。现在，通过快速分析非洲采用ACT前后感染之间的遗传差异的数量和质量的技术进步，获取这种信息是可能的。因此，该项目寻求更好地了解导致抗疟疾耐药性的过程，方法是利用新技术的进步，全面研究从ACTs之前到西非国家冈比亚使用这种寄生虫五年期间的遗传差异。该地区药物的使用和低水平的传播有利于寄生虫产生抗药性。这些信息将有助于确定耐药性的遗传决定因素和对药物不起反应的寄生虫传播的社区。然后，这项研究将使用实验室中的方法来确定这些寄生虫对正在使用的药物的敏感性。那些对药物有抗药性的人将使用遗传学工具进行分析。这项研究还将研究如何清除正在接受ACTS治疗的感染者身上的寄生虫。带有在治疗过程中未能从血液中清除的寄生虫的社区将成为进一步基因分析的重点，以确定基因变化是否对这种行为负责。该项目将利用MRC单位、冈比亚和北方伙伴(英国和美国)之间在分析和技术转让方面的出色合作。这项研究将持续48个月，并将在实施不同的疫苗、药物和媒介干预措施的情况下，为非洲次区域未来的人口遗传学研究建设能力。该项目的发现还应该让政策制定者了解制定新的干预战略，该战略将纳入被研究人群的具体情况。这将使我作为西非一名独立的基因组科学家在这一领域的研究生涯得到发展。

Malaria disease from infection with the parasite Plasmodium falciparum remains an important global health problem. More information is needed to continue developing new ways of controlling the disease which infects predominantly impoverished endemic countries in sub Saharan Africa. Some of this includes information on genetic differences between different types of the parasites, particularly those that don't respond to the drugs presently used for treatment. Malaria has developed resistance to previously available cheap drugs like chloroquine and Fansidar. Due to this strong ability to develop new ways of evading drugs and continuing transmission of infection and cause disease in other individuals, it now requires the use of new drug combinations containing the compound artemisinin (ART) to treat infections. These new drug combinations (ACTs) are more expensive and represent the only most effective treatment of malaria infections in sub saharan Africa. However, there are indications that some infections with malaria in South East Asia are not treated as effectively as expected with these new drug combinations indicating that the parasites may already be developing new mechanisms to resist the effect of these drug combinations. If this alarming development were to continue and spread to Africa it will be a big blow to the efforts to reduce the burden of malaria in the continent that bears 90% of the malaria burden. For the scientific community to be ready for such an eventuality, it is important to start looking at factors that will enable these parasites that resist drug action to develop and spread in affected sub Saharan Arican populations. Some of these factors include the the ability of some parasites to tolerate drug concentrations that will normally kill them. The challenge in gaining understanding of the complex processes in the parasite that create the conditions for drug resistance is the requirement for large amount of data from populations where these drugs have been used for some time. Aquiring such information can now be possible by advancements in technologies for rapidly analysing the quantity and quality of genetic differences between infections before and since ACT adoption in Africa. This project therefore seeks a better understanding of the processes that lead to antimalarial drug resistance by taking advantage of advances in new technologies to comprehensively study genetic differences in the parasites from the period before ACTs through five years of its use in the West African state, The Gambia. Use of drugs and the low level of transmission in this region is favorable for parasites to develp resistance. This information will enable the identification of genetics determinants of drug resistance and communities in which parasites that donot respond to drug are transmitted. The study will then employ methods in the lab to determine the sensitivity of these parasites to drugs being used. Those that are resistant to drugs will be analysed using genetics tools. The study will also look at how parasites will be cleared from infected people being treated with ACTs. Communities with parasites that fail to clear from blood during treatment will be the focus of further genetic analysis to determine if genetic changes are responsible for this kind of behaviour. This project will make use of excellent collaboration between MRC Unit, The Gambia and Northern partners (UK and US) for analysis and technology transfer. The study will last for a period of 48 months and will build capacity for future population genetic research in the African sub region given the different vaccine, drug and vector interventions being implimented. The findings from the project should also inform policy makers on developing new intervention strategies that will incorporate the percularities of populations studied. It will enable the developmeent of my research career in this field as an independent genomics scientist in West Africa.