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

由恶性疟原虫感染引起的疟疾仍然是一个重要的全球卫生问题。需要更多的信息，以继续发展控制这种主要感染撒哈拉以南非洲贫穷流行国家的疾病的新方法。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。疟疾已经对以前可以获得的廉价药物如氯喹和范西达产生了抗药性。由于这种开发逃避药物和继续传播感染并在其他个体中引起疾病的新方法的强大能力，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。这些新的联合药物更为昂贵，是撒哈拉以南非洲地区唯一最有效的疟疾感染治疗方法。然而，有迹象表明，东南亚的一些疟疾感染并没有像预期的那样得到这些新药物组合的有效治疗，这表明寄生虫可能已经在发展新的机制来抵抗这些药物组合的影响。如果这一令人震惊的事态发展继续下去并蔓延到非洲，这将对在非洲减轻疟疾负担的努力造成重大打击，因为非洲承担着90%的疟疾负担。为了让科学界为这种可能性做好准备，重要的是要开始研究使这些抵抗药物作用的寄生虫能够在受影响的撒哈拉以南非洲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。要了解寄生虫体内产生耐药性条件的复杂过程，面临的挑战是需要从使用这些药物已有一段时间的人群中获得大量数据。通过快速分析非洲采用青蒿素联合疗法前后感染之间遗传差异的数量和质量的技术进步，现在有可能获得这类信息。因此，该项目寻求更好地了解导致抗疟药耐药性的过程，方法是利用新技术的进步，全面研究从以青蒿素为基础的联合疗法出现之前到西非国家冈比亚使用青蒿素5年期间寄生虫的遗传差异。该地区药物的使用和低传播水平有利于寄生虫产生耐药性。这一信息将有助于确定耐药性的遗传决定因素以及对药物无反应的寄生虫传播的社区。然后，该研究将在实验室中使用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将使用遗传学工具进行分析。这项研究还将研究如何从接受以青蒿素为基础的联合治疗的感染者身上清除寄生虫。在治疗期间未能从血液中清除寄生虫的社区将成为进一步遗传分析的重点，以确定遗传变化是否对这种行为负责。该项目将利用MRC单位、冈比亚和北方合作伙伴（英国和美国）之间在分析和技术转让方面的良好合作。这项研究将持续48个月，鉴于正在实施不同的疫苗、药物和媒介干预措施，它将为非洲分区域未来的人口遗传研究建立能力。该项目的调查结果还应为决策者提供信息，以便制定将所研究人口的特殊性纳入其中的新的干预战略。这将使我作为西非独立的基因组学科学家在这一领域的研究事业得以发展。

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.