2. Academic Validation
  3. Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

  • Cell Host Microbe. 2017 Dec 13;22(6):766-776.e4. doi: 10.1016/j.chom.2017.11.005.
Min Zhang 1,  Julio Gallego-Delgado 2,  Cristina Fernandez-Arias 3,  Norman C Waters 4,  Ana Rodriguez 2,  Moriya Tsuji 3,  Ronald C Wek 5,  Victor Nussenzweig 6,  William J Sullivan Jr 7
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pathology, New York University School of Medicine, New York, NY, USA; HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA. Electronic address: zhanmin@iu.edu.
  • 2 Division of Parasitology, Department of Microbiology, New York University School of Medicine, New York, NY, USA.
  • 3 HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
  • 4 Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
  • 5 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 6 Department of Pathology, New York University School of Medicine, New York, NY, USA.
  • 7 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: wjsulliv@iu.edu.
PMID: 29241041 DOI: 10.1016/j.chom.2017.11.005
Abstract

Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent Infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown. Here, we report that ART treatment results in phosphorylation of the Parasite eukaryotic initiation factor-2α (eIF2α), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2α correlates with high rates of recrudescence following ART, and inhibiting eIF2α dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2α phosphorylation is mediated by the Plasmodium eIF2α kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent Infection.

Keywords

PK4; Plasmodium; artemisinin; eIF2α; endoplasmic reticulum; latency; recrudescence; resistance; translation.

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