Artemisinin resistance in rodent malaria--mutation in the AP2 adaptor ?-chain suggests involvement of endocytosis and membrane protein trafficking
Language: 
English
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 ?-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.

Author(s): 
Henriques, Gisela
Martinelli, Axel
Rodrigues, Louise
Modrzynska, Katarzyna
Fawcett, Richard
Houston, Douglas R.
Borges, Sofia T.
D'Alessandro, Umberto
Tinto, Halidou
Karema, Corine
Hunt, Paul
Cravo, Pedro
Item Type: 
Journal Article
Publication Title: 
Malaria Journal
Journal Abbreviation: 
Malar. J.
Publication Date: 
2013
Publication Year: 
2013
Pages: 
118
Volume: 
12
ISSN: 
1475-2875
DOI: 
10.1186/1475-2875-12-118
Library Catalog: 
PubMed
Extra: 
PMID: 23561245 PMCID: PMC3655824

Turabian/Chicago Citation

Gisela Henriques, Axel Martinelli, Louise Rodrigues, Katarzyna Modrzynska, Richard Fawcett, Douglas R. Houston, Sofia T. Borges, Umberto D'Alessandro, Halidou Tinto, Corine Karema, Paul Hunt and Pedro Cravo. 2013. "Artemisinin resistance in rodent malaria--mutation in the AP2 adaptor ?-chain suggests involvement of endocytosis and membrane protein trafficking." Malaria Journal 12: 118. 10.1186/1475-2875-12-118.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1186/1475-2875-12-118 | issn = 1475-2875 | volume = 12 | pages = 118 | last = Henriques | first = Gisela | coauthors = Martinelli, Axel, Rodrigues, Louise, Modrzynska, Katarzyna, Fawcett, Richard, Houston, Douglas R., Borges, Sofia T., D'Alessandro, Umberto, Tinto, Halidou, Karema, Corine, Hunt, Paul, Cravo, Pedro | title = Artemisinin resistance in rodent malaria--mutation in the AP2 adaptor ?-chain suggests involvement of endocytosis and membrane protein trafficking | journal = Malaria Journal | date = 2013 | pmid = | pmc = }} </ref>