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

冈比亚的恶性疟原虫抗疟疾耐药性：通过回顾性全基因组方法鉴定潜在的遗传标记

• 批准号: MC_EX_MR/K02440X/1
• 负责人: Alfred Ngwa
• 金额: $ 77.33万
• 依托单位: MRC Unit the Gambia
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_EX_MR%2FK02440X%2F1
• 关键词: Plasmodium; falciparum; anti; malarial; drug

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.

由寄生虫恶性疟原虫感染引起的疟疾疾病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困流行国家。其中一些包括不同类型寄生虫之间遗传差异的信息，特别是那些对目前用于治疗的药物没有反应的寄生虫。疟疾已经对以前可用的廉价药物如氯喹和凡西达产生了抗药性。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，现在需要使用含有青蒿素化合物的新药物组合来治疗感染。这些新的药物组合（ACTs）更昂贵，是撒哈拉以南非洲唯一最有效的疟疾治疗方法。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有效地治疗这些新的药物组合，这表明寄生虫可能已经开发了新的机制来抵抗这些药物组合的作用。如果这种令人震惊的发展继续下去并蔓延到非洲，这将是对非洲大陆减轻疟疾负担的努力的一个沉重打击，非洲大陆承担了90%的疟疾负担。对于科学界来说，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耐受通常会杀死它们的药物浓度的能力。了解寄生虫中产生耐药性条件的复杂过程的挑战是需要来自这些药物已使用一段时间的人群的大量数据。由于技术进步，现在可以快速分析非洲采用青蒿素综合疗法前后感染之间遗传差异的数量和质量，从而有可能获得此类信息。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ACT之前到西非国家使用ACT五年期间寄生虫的遗传差异。冈比亚。本地区药物的使用和传播水平低有利于寄生虫产生耐药性。这些信息将有助于确定耐药性的遗传决定因素和传播对药物无反应的寄生虫的社区。然后，该研究将采用实验室方法来确定这些寄生虫对所使用药物的敏感性。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ACT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是导致这种行为的原因。该项目将利用湄公河委员会、冈比亚和北方伙伴（英国和美国）之间的良好合作进行分析和技术转让。这项研究将持续48个月，并将在非洲次区域建立未来人口遗传研究的能力，因为正在实施不同的疫苗，药物和媒介干预措施。该项目的调查结果还应使决策者了解如何制定新的干预战略，其中将纳入所研究人口的特殊性。它将使我在这一领域的研究事业发展成为西非独立的基因组学科学家。

项目成果

Exceptionally long-range haplotypes in Plasmodium falciparum chromosome 6 maintained in an endemic African population.

• DOI: 10.1186/s12936-016-1560-7
• 发表时间: 2016-10-21
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Amambua-Ngwa A;Danso B;Worwui A;Ceesay S;Davies N;Jeffries D;D'Alessandro U;Conway D
• 通讯作者: Conway D

Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1.

• DOI: 10.1038/s41564-023-01377-z
• 发表时间: 2023-07
• 期刊: NATURE MICROBIOLOGY
• 影响因子: 28.3
• 作者: Amambua-Ngwa, Alfred;Button-Simons, Katrina A. A.;Li, Xue;Kumar, Sudhir;Brenneman, Katelyn Vendrely;Ferrari, Marco;Checkley, Lisa A. A.;Haile, Meseret T. T.;Shoue, Douglas A. A.;McDew-White, Marina;Tindall, Sarah M. M.;Reyes, Ann;Delgado, Elizabeth;Dalhoff, Haley;Larbalestier, James K. K.;Amato, Roberto;Pearson, Richard D. D.;Taylor, Alexander B. B.;Nosten, Francois H.;D'Alessandro, Umberto;Kwiatkowski, Dominic;Cheeseman, Ian H. H.;Kappe, Stefan H. I.;Avery, Simon V. V.;Conway, David J. J.;Vaughan, Ashley M. M.;Ferdig, Michael T. T.;Anderson, Timothy J. C.
• 通讯作者: Anderson, Timothy J. C.

Long-distance transmission patterns modelled from SNP barcodes of Plasmodium falciparum infections in The Gambia

• DOI: 10.1038/s41598-019-49991-4
• 发表时间: 2019-09-18
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Amambua-Ngwa, Alfred;Jeffries, David;D'Alessandro, Umberto
• 通讯作者: D'Alessandro, Umberto

Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia.

• DOI: 10.1128/aac.00759-17
• 发表时间: 2017-12
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Amambua-Ngwa A;Okebe J;Mbye H;Ceesay S;El-Fatouri F;Joof F;Nyang H;Janha R;Affara M;Ahmad A;Kolly O;Nwakanma D;D'Alessandro U
• 通讯作者: D'Alessandro U

Molecular markers for artemisinin and partner drug resistance in natural Plasmodium falciparum populations following increased insecticide treated net coverage along the slope of mount Cameroon: cross-sectional study.

• DOI: 10.1186/s40249-017-0350-y
• 发表时间: 2017-11-06
• 期刊: Infectious diseases of poverty
• 影响因子: 8.1
• 作者: Apinjoh TO;Mugri RN;Miotto O;Chi HF;Tata RB;Anchang-Kimbi JK;Fon EM;Tangoh DA;Nyingchu RV;Jacob C;Amato R;Djimde A;Kwiatkowski D;Achidi EA;Amambua-Ngwa A
• 通讯作者: Amambua-Ngwa A