Artemisinin resistance in rodent malaria - mutation in the AP2 adaptor μ-chain suggests involvement of endocytosis and membrane protein trafficking

Malaria Journal

Research

Halidou Tinto¹  Louise Rodrigues²  Sofia T Borges²  Axel Martinelli³  Pedro Cravo⁴  Gisela Henriques⁵  Richard Fawcett⁶  Paul Hunt⁷  Katarzyna Modrzynska⁸  Douglas R Houston⁹  Corine Karema^1,10  Umberto d’Alessandro^1,11 

[1] Centre Muraz/Institut de Recherche en Sciences de la Santé, Bobo Dioulasso, Burkina Faso;Centro de Malaria & Doenças Tropicais, LA/IHMT/Universidade Nova de Lisboa, Lisbon, Portugal;Centro de Malaria & Doenças Tropicais, LA/IHMT/Universidade Nova de Lisboa, Lisbon, Portugal;Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK;Wellcome Trust Sanger Institute, Hinxton, Cambridgshire, UK;Centro de Malaria & Doenças Tropicais, LA/IHMT/Universidade Nova de Lisboa, Lisbon, Portugal;Instituto de Patologia Tropical e Saúde Pública/Universidade Federal de Goiás, CAPES/Brazil, 74605-050, Goiânia, Brazil;Centro de Malaria & Doenças Tropicais, LA/IHMT/Universidade Nova de Lisboa, Lisbon, Portugal;London School of Hygiene and Tropical Medicine, Room 490, Keppel Street, WC1E 7HT, London, UK;Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK;Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK;Centre of Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, UK;Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK;Wellcome Trust Sanger Institute, Hinxton, Cambridgshire, UK;Institute for Structural and Molecular Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK;National Malaria Control Programme, Kigali, Rwanda;Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium;

关键词: Malaria;    Artemisinin;    Drug resistance;    Genomics;    Plasmodium chabaudi;    Mutation;    Endocytic machinery;   

DOI  :  10.1186/1475-2875-12-118

 received in 2012-12-05, accepted in 2013-02-26,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe control of malaria, caused by Plasmodium falciparum, is hampered by the relentless evolution of drug resistance. Because artemisinin derivatives are now used in the most effective anti-malarial therapy, resistance to artemisinin would be catastrophic. Indeed, studies suggest that artemisinin resistance has already appeared in natural infections. Understanding the mechanisms of resistance would help to prolong the effective lifetime of these drugs. Genetic markers of resistance are therefore required urgently. Previously, a mutation in a de-ubiquitinating enzyme was shown to confer artemisinin resistance in the rodent malaria parasite Plasmodium chabaudi.MethodsHere, for a mutant P. chabaudi malaria parasite and its immediate progenitor, the in vivo artemisinin resistance phenotypes and the mutations arising using Illumina whole-genome re-sequencing were compared.ResultsAn increased artemisinin resistance phenotype is accompanied by one non-synonymous substitution. The mutated gene encodes the μ-chain of the AP2 adaptor complex, a component of the endocytic machinery. Homology models indicate that the mutated residue interacts with a cargo recognition sequence. In natural infections of the human malaria parasite P. falciparum, 12 polymorphisms (nine SNPs and three indels) were identified in the orthologous gene.ConclusionAn increased artemisinin-resistant phenotype occurs along with a mutation in a functional element of the AP2 adaptor protein complex. This suggests that endocytosis and trafficking of membrane proteins may be involved, generating new insights into possible mechanisms of resistance. The genotypes of this adaptor protein can be evaluated for its role in artemisinin responses in human infections of P. falciparum.

【 授权许可】

CC BY   
© Henriques et al.; licensee BioMed Central Ltd. 2013