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Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins.

Authors :
Xie, Stanley C.
Dogovski, Con
Hanssen, Eric
Chiu, Francis
Tuo Yang
Crespo, Maria P.
Stafford, Che
Batinovic, Steven
Teguh, Silvia
Charman, Susan
Klonis, Nectarios
Tilley, Leann
Source :
Journal of Cell Science; Jan2016, Vol. 129 Issue 2, p406-416, 11p
Publication Year :
2016

Abstract

Current first-line artemisinin antimalarials are threatened by the emergence of resistant Plasmodium falciparum. Decreased sensitivity is evident in the initial (early ring) stage of intraerythrocytic development, meaning that it is crucial to understand the action of artemisinins at this stage. Here, we examined the roles of iron (Fe) ions and haem in artemisinin activation in early rings using Fe ion chelators and a specific haemoglobinase inhibitor (E64d). Quantitative modelling of the antagonism accounted for its complex dependence on the chemical features of the artemisinins and on the drug exposure time, and showed that almost all artemisinin activity in early rings (>80%) is due to haem-mediated activation. The surprising implication that haemoglobin uptake and digestion is active in early rings is supported by identification of active haemoglobinases (falcipains) at this stage. Genetic down-modulation of the expression of the two main cysteine protease haemoglobinases, falcipains2and3,renders early ring stage parasites resistant to artemisinins. This confirms the important role of haemoglobin-degrading falcipains in artemisinin activation, and shows that changes in the rate of artemisinin activation could mediate high-level artemisinin resistance. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00219533
Volume :
129
Issue :
2
Database :
Complementary Index
Journal :
Journal of Cell Science
Publication Type :
Academic Journal
Accession number :
112353848
Full Text :
https://doi.org/10.1242/jcs.178830