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

Xie, SC; Dogovski, C; Hanssen, E; Chiu, F; Yang, T; Crespo, MP; Stafford, C; Batinovic, S; Teguh, S; Charman, S; Klonis, N; Tilley, L

Author(s): Xie, SC; Dogovski, C; Hanssen, E; Chiu, F; Yang, T; Crespo, MP; Stafford, C; Batinovic, S; Teguh, S; Charman, S; Klonis, N; Tilley, L;
Details: Publication Year 2016-01-15,Volume 129,Issue #2,Page 406-416
Journal Title: J Cell Sci
Publication Type: Journal Article
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, making it critical to understand the action of artemisinins at this stage. We examined the roles of iron and haem in artemisinin activation in early rings using iron chelators and a specific haemoglobinase inhibitor (E64d). Quantitative modelling of the antagonism accounted for its complex dependence on 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, falcipains 2 and 3, 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.
Publisher: COB
Research Division(s): Cell Signalling And Cell Death
PubMed ID: 26675237
Publisher's Version: https://doi.org/10.1242/jcs.178830
Open Access at Publisher's Site: http://jcs.biologists.org/content/early/2015/12/15/jcs.178830.long
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-01-13 02:34:13

Last Modified: 2016-01-21 09:12:03