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

G. Henriques, A. Martinelli, L. Rodrigues, K. Modrzynska, R. Fawcett, D.R. Houston, S.T. Borges, Umberto D'Alessandro, H. Tinto, C. Karema, P. Hunt, P. Cravo

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Abstract

BACKGROUND: The 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. METHODS: Here, 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. RESULTS: An increased artemisinin resistance phenotype is accompanied by one non-synonymous substitution. The mutated gene encodes the mu-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. CONCLUSION: An 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.
Original languageEnglish
JournalMalaria Journal
Volume12
Issue number118
Pages (from-to)1-15
Number of pages15
ISSN1475-2875
DOIs
Publication statusPublished - 2013

Keywords

  • Protozoal diseases
  • Malaria
  • Plasmodium falciparum
  • Plasmodium chabaudi
  • Comparison
  • Drug resistance
  • Artemisinins
  • In vivo
  • Phenotypes
  • Mutations
  • Polymorphism
  • Proteins

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