Host Cell Metabolism Contributes to Delayed-Death Kinetics of Apicoplast Inhibitors in Toxoplasma gondii

Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01646-18. doi: 10.1128/AAC.01646-18. Print 2019 Feb.

Abstract

Toxoplasma gondii and related human parasites contain an essential plastid organelle called the apicoplast. Clinically used antibiotics and other inhibitors that disrupt apicoplast biogenesis cause a mysterious "delayed-death" phenotype in which parasite growth is unaffected during the first lytic cycle of inhibitor treatment but is severely inhibited in the second lytic cycle even after drug removal. Critical to understanding the complex downstream cellular effects of these drug classes are the timing of apicoplast loss during inhibitor treatment and how it relates to this peculiar growth phenotype. Here we show that, upon treatment with diverse classes of apicoplast inhibitors, newly replicated T. gondii parasites in the first lytic cycle initially form apicoplasts with defects in protein import or genome replication and eventually fail to inherit the apicoplast altogether. Despite the accumulation of parasites with defective or missing apicoplasts, growth is unaffected during the first lytic cycle, as previously observed. Strikingly, concomitant inhibition of host cell isoprenoid biosynthesis results in growth inhibition in the first lytic cycle and unmasks the apicoplast defects. These results suggest that defects in and even the complete loss of the apicoplast in T. gondii are partially rescued by scavenging of host cell metabolites, leading to death that is delayed. Our findings uncover host cell interactions that can alleviate apicoplast inhibition and highlight key differences in delayed-death inhibitors between T. gondii and Plasmodium falciparum.

Keywords: Plasmodium falciparum; Toxoplasma gondii; antimalarial agents; antiparasitic agents; apicoplast; host-parasite relationship.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / therapeutic use*
  • Antiparasitic Agents / therapeutic use
  • Apicoplasts / drug effects*
  • Cell Line
  • Flow Cytometry
  • Host-Parasite Interactions
  • Humans
  • Immunoblotting
  • Kinetics
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / pathogenicity
  • Real-Time Polymerase Chain Reaction
  • Toxoplasma / drug effects*
  • Toxoplasma / parasitology

Substances

  • Antimalarials
  • Antiparasitic Agents