Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

Min Zhang, Julio Gallego-Delgado, Cristina Fernandez-Arias, Norman C. Waters, Ana Rodriguez, Moriya Tsuji, Ronald Wek, Victor Nussenzweig, William Sullivan

Research output: Contribution to journalArticle

12 Citations (Scopus)

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. The antimalarial drug artemisinin is associated with a high frequency of recrudescent infection. Zhang et al. identified that artemisinin induces latency through Plasmodium eukaryotic initiation factor 2α (eIF2α) phosphorylation. Inhibiting the Plasmodium eIF2α kinase PK4 blocks parasites from entering latency and abolishes recrudescence after artemisinin therapy.

Original languageEnglish (US)
Pages (from-to)766-776.e4
JournalCell Host and Microbe
Volume22
Issue number6
DOIs
StatePublished - Dec 13 2017

Fingerprint

Eukaryotic Initiation Factor-2
Plasmodium
Phosphotransferases
Parasites
Phosphorylation
Antimalarials
Recurrence
Infection
artemisinine
Treatment Failure
Pharmacology

Keywords

  • artemisinin
  • eIF2α
  • endoplasmic reticulum
  • latency
  • PK4
  • Plasmodium
  • recrudescence
  • resistance
  • translation

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

Cite this

Zhang, M., Gallego-Delgado, J., Fernandez-Arias, C., Waters, N. C., Rodriguez, A., Tsuji, M., ... Sullivan, W. (2017). Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency. Cell Host and Microbe, 22(6), 766-776.e4. https://doi.org/10.1016/j.chom.2017.11.005

Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency. / Zhang, Min; Gallego-Delgado, Julio; Fernandez-Arias, Cristina; Waters, Norman C.; Rodriguez, Ana; Tsuji, Moriya; Wek, Ronald; Nussenzweig, Victor; Sullivan, William.

In: Cell Host and Microbe, Vol. 22, No. 6, 13.12.2017, p. 766-776.e4.

Research output: Contribution to journalArticle

Zhang, M, Gallego-Delgado, J, Fernandez-Arias, C, Waters, NC, Rodriguez, A, Tsuji, M, Wek, R, Nussenzweig, V & Sullivan, W 2017, 'Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency', Cell Host and Microbe, vol. 22, no. 6, pp. 766-776.e4. https://doi.org/10.1016/j.chom.2017.11.005
Zhang M, Gallego-Delgado J, Fernandez-Arias C, Waters NC, Rodriguez A, Tsuji M et al. Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency. Cell Host and Microbe. 2017 Dec 13;22(6):766-776.e4. https://doi.org/10.1016/j.chom.2017.11.005
Zhang, Min ; Gallego-Delgado, Julio ; Fernandez-Arias, Cristina ; Waters, Norman C. ; Rodriguez, Ana ; Tsuji, Moriya ; Wek, Ronald ; Nussenzweig, Victor ; Sullivan, William. / Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency. In: Cell Host and Microbe. 2017 ; Vol. 22, No. 6. pp. 766-776.e4.
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