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Liver stage malaria infection is controlled by host regulators of lipid peroxidation

Heather S Kain1, Elizabeth K K Glennon1,2, Kamalakannan Vijayan1,2

  • 1Center for Infectious Disease Research, Seattle Biomedical Research Institute, Seattle, WA, USA.

Cell Death and Differentiation
|May 9, 2019
PubMed

Insights

Blocking the SLC7a11-GPX4 pathway in host cells eliminates Plasmodium liver stage parasites by increasing lipid peroxides. This pathway is critical for controlling malaria parasite infection during its liver stage.

Area of Science:

  • Immunology
  • Parasitology
  • Cell Biology

Background:

  • Host control mechanisms during Plasmodium liver infection are not well understood.
  • The SLC7a11-GPX4 pathway is linked to reactive oxygen species, lipid peroxidation, and ferroptosis.

Purpose of the Study:

  • To investigate the role of the SLC7a11-GPX4 pathway in controlling Plasmodium liver stage infection.
  • To determine how host factors influence parasite burden in the liver.

Main Methods:

  • Inhibition of GPX4 and SLC7a11 in host cells.
  • Knockdown of NOX1 and TFR1, negative regulators of the pathway.
  • Assessment of Plasmodium liver stage parasite burden.
  • Evaluation of P53's role in parasite control under various conditions.
  • Treatment with SLC7a11 inhibitors Erastin and Sorafenib.

Main Results:

  • Blocking GPX4 or SLC7a11 significantly reduced Plasmodium liver stage infection.
  • Inhibition of NOX1 and TFR1 increased liver stage infection.
  • Increased P53 levels failed to control parasite burden when the SLC7a11-GPX4 pathway was compromised or ROS scavenging was employed.
  • SLC7a11 inhibitors Erastin and Sorafenib reduced Plasmodium infection.
  • Elevated lipid peroxides localized within the parasite, leading to parasite elimination.

Conclusions:

  • The host SLC7a11-GPX4 pathway is essential for controlling Plasmodium liver stage infection.
  • Targeting this pathway selectively increases lipid peroxides in infected cells, eliminating liver stage parasites.
  • This pathway represents a potential therapeutic target for malaria treatment.

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