Plasmodium falciparum Artemisinin Resistance: The Effect of Heme, Protein Damage, and Parasite Cell Stress Response

Melissa R. Rosenthal, Caroline L. Ng

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations

Abstract

Despite a significant decline in morbidity and mortality over the last two decades, in 2018 there were 228 million reported cases of malaria and 405000 malaria-related deaths. Artemisinin, the cornerstone of artemisinin-based combination therapies, is the most potent drug in the antimalarial armamentarium against falciparum malaria. Heme-mediated activation of artemisinin and its derivatives results in widespread parasite protein alkylation, which is thought to lead to parasite death. Alarmingly, cases of decreased artemisinin efficacy have been widely detected across Cambodia and in neighboring countries, and a few cases have been reported in the Guiana Shield, India, and Africa. The grim prospect of widespread artemisinin resistance propelled a concerted effort to understand the mechanisms of artemisinin action and resistance. The identification of genetic markers and the knowledge of molecular mechanisms underpinning artemisinin resistance allow prospective surveillance and inform future drug development strategies, respectively. Here, we highlight recent advances in our understanding of how parasite vesicle trafficking, hemoglobin digestion, and cell stress responses contribute to artemisinin resistance.

Original languageEnglish (US)
Pages (from-to)1599-1614
Number of pages16
JournalACS infectious diseases
Volume6
Issue number7
DOIs
StatePublished - Jul 10 2020

Keywords

  • Kelch13
  • Plasmodium falciparum
  • artemisinin
  • cell stress response
  • hemoglobin
  • proteasome
  • resistance
  • unfolded protein response
  • vesicle trafficking

ASJC Scopus subject areas

  • Infectious Diseases

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