Novel Genetic Mechanism of Artemisinin Resistance for Malaria

青蒿素抗疟疾的新遗传机制

• 批准号: 10201429
• 负责人: Daniel L HARTL
• 金额: $ 69.49万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201429
• 关键词: Africa; African; Alleles; Artemisinins; Asia; Asians; CRISPR/Cas technology; Cambodia; Cambodian; Child; Clinical; Collaborations; Combined Modality Therapy; Evolution; Exposure to; Family; Frequencies; Genes; Genetic; In Vitro; Incidence; Individual; Infection; Laboratories; Malaria; Measures; Molecular; Mutation; Other Genetics; Parasites; Phenotype; Population; Population Genetics; Proteins; Quality Control; Reporting; Resistance; Role; Sampling; Senegal; Sentinel; Site; Southeastern Asia; Structure; Tanzania; Testing; Validation; WD Repeat; base; biological adaptation to stress; coronin protein; deep sequencing; early detection biomarkers; gene interaction; genetic analysis; mutant; novel; novel therapeutics; pressure; prevent; resistance gene; resistant strain

Recent progress in malaria control has reduced the incidence and saved the lives of hundreds of thousands of children, but effective strategies depend on a combination of measures that includes special emphasis on artemisinin-based combination therapies (ACTs). The predicted dire consequences of the evolution and spread of artemisinin (ART) resistance have been borne out tragically in Southeast Asia, where ART resistance evolved quickly and spread rapidly. The ART-resistance determinants reside in the propeller domain of the Pfkelch13 locus (K13), which is thought to facilitate protein quality control and modulate stress responses. Importantly, the K13 determinant was first identified through five-year in vitro selection and sequencing of a resistant strain from Tanzania; K13 was only later confirmed in the field in Southeast Asia. Were ART resistance to take hold and spread in Africa it would be truly catastrophic. Why it has not is open to speculation, however one possibility is because K13 effects are strongly dependent on genetic background, and there are significant genetic differences between African parasite and SE Asian lineages. But persistent, strong selection pressure from ART treatment in Africa will—as every evolutionary biologist knows—result almost inevitably in the evolution of resistance determinants in Africa. Based on the hypothesis that ART resistance might depend on genetic background, four years ago (prior to the K13 report) we began selecting independent replicate lines of parasites from Senegal. We are now able to report that high-level resistance has evolved in three independent lines. Our ART resistance lines show all of the known in vitro phenotypic hallmarks of clinical ART resistance, but they are not K13 mutants! Remarkably, three independent selected lines each contain a different mutation in the gene PF3D7_1251200, which encodes Coronin, one of a family of WD-repeat proteins containing a beta propeller structure. The importance of Pf1251200 has already been demonstrated experimentally in our laboratory using CRISPR/Cas9 replacements. These findings demonstrate the existence of at least two distinct genetic mechanisms of ART resistance. Investigating the Pf1251200 mutants and their interactions with K13 and other genes will help elucidate the mechanism of action of artemisinin, which is still unknown, and perhaps more important will provide markers for early detection of non-K13 ART resistance in clinical settings in Africa as well as SE Asia where a significant proportion of ART-resistant isolates have no mutations in K13.

最近在疟疾控制方面取得的进展降低了发病率并挽救了数百人的生命

项目成果

Natural selection constrains neutral diversity across a wide range of species.

• DOI: 10.1371/journal.pbio.1002112
• 发表时间: 2015-04
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Corbett-Detig RB;Hartl DL;Sackton TB
• 通讯作者: Sackton TB

Genetic surveillance detects both clonal and epidemic transmission of malaria following enhanced intervention in Senegal.

• DOI: 10.1371/journal.pone.0060780
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Daniels R;Chang HH;Séne PD;Park DC;Neafsey DE;Schaffner SF;Hamilton EJ;Lukens AK;Van Tyne D;Mboup S;Sabeti PC;Ndiaye D;Wirth DF;Hartl DL;Volkman SK
• 通讯作者: Volkman SK

Genetic evidence that the Makira region in northeastern Madagascar is a hotspot of malaria transmission.

• DOI: 10.1186/s12936-016-1644-4
• 发表时间: 2016-12-20
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Rice BL;Golden CD;Anjaranirina EJ;Botelho CM;Volkman SK;Hartl DL
• 通讯作者: Hartl DL

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations.

• DOI: 10.1016/j.ijpddr.2021.07.004
• 发表时间: 2021-12
• 期刊: International journal for parasitology. Drugs and drug resistance
• 作者: Ndiaye YD;Hartl DL;McGregor D;Badiane A;Fall FB;Daniels RF;Wirth DF;Ndiaye D;Volkman SK
• 通讯作者: Volkman SK

A broad analysis of resistance development in the malaria parasite.

对疟原虫耐药性发展的广泛分析。

• DOI: 10.1038/ncomms11901
• 发表时间: 2016-06-15
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Corey VC;Lukens AK;Istvan ES;Lee MCS;Franco V;Magistrado P;Coburn-Flynn O;Sakata-Kato T;Fuchs O;Gnädig NF;Goldgof G;Linares M;Gomez-Lorenzo MG;De Cózar C;Lafuente-Monasterio MJ;Prats S;Meister S;Tanaseichuk O;Wree M;Zhou Y;Willis PA;Gamo FJ;Goldberg DE;Fidock DA;Wirth DF;Winzeler EA
• 通讯作者: Winzeler EA