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

Stanley C. Xie, Con Dogovski, Eric Hanssen, Francis Chiu, Tuo Yang, Maria P. Crespo, Che Stafford, Steven Batinovic, Silvia Teguh, Susan Charman, Nectarios Klonis, Leann Tilley

Research output: Contribution to journalArticleResearchpeer-review

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, 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.

Original languageEnglish
Pages (from-to)406-416
Number of pages11
JournalJournal of Cell Science
Volume129
Issue number2
DOIs
Publication statusPublished - 2016

Keywords

  • Artemisinin
  • Falcipains
  • Haemoglobin degradation
  • Malaria
  • Plasmodium
  • Resistance

Cite this

Xie, Stanley C. ; Dogovski, Con ; Hanssen, Eric ; Chiu, Francis ; Yang, Tuo ; Crespo, Maria P. ; Stafford, Che ; Batinovic, Steven ; Teguh, Silvia ; Charman, Susan ; Klonis, Nectarios ; Tilley, Leann. / Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins. In: Journal of Cell Science. 2016 ; Vol. 129, No. 2. pp. 406-416.
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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, 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.",
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author = "Xie, {Stanley C.} and Con Dogovski and Eric Hanssen and Francis Chiu and Tuo Yang and Crespo, {Maria P.} and Che Stafford and Steven Batinovic and Silvia Teguh and Susan Charman and Nectarios Klonis and Leann Tilley",
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Xie, SC, Dogovski, C, Hanssen, E, Chiu, F, Yang, T, Crespo, MP, Stafford, C, Batinovic, S, Teguh, S, Charman, S, Klonis, N & Tilley, L 2016, 'Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins' Journal of Cell Science, vol. 129, no. 2, pp. 406-416. https://doi.org/10.1242/jcs.178830

Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins. / Xie, Stanley C.; Dogovski, Con; Hanssen, Eric; Chiu, Francis; Yang, Tuo; Crespo, Maria P.; Stafford, Che; Batinovic, Steven; Teguh, Silvia; Charman, Susan; Klonis, Nectarios; Tilley, Leann.

In: Journal of Cell Science, Vol. 129, No. 2, 2016, p. 406-416.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins

AU - Xie, Stanley C.

AU - Dogovski, Con

AU - Hanssen, Eric

AU - Chiu, Francis

AU - Yang, Tuo

AU - Crespo, Maria P.

AU - Stafford, Che

AU - Batinovic, Steven

AU - Teguh, Silvia

AU - Charman, Susan

AU - Klonis, Nectarios

AU - Tilley, Leann

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