Analysis of monensin sensitivity in toxoplasma gondii reveals autophagy as a mechanism for drug induced death

Mark D. Lavine, Gustavo Arrizabalaga

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Understanding the mechanisms by which anti-parasitic drugs alter the physiology and ultimately kill is an important area of investigation. Development of novel parasitic drugs, as well as the continued utilization of existing drugs in the face of resistant parasite populations, requires such knowledge. Here we show that the anti-coccidial drug monensin kills Toxoplasma gondii by inducing autophagy in the parasites, a novel mechanism of cell death in response to an antimicrobial drug. Monensin treatment results autophagy, as shown by translocation of ATG8 to autophagosomes, as well as causing marked morphological changes in the parasites' mitochondria. Use of the autophagy inhibitor 3-methyladenine blocks autophagy and mitochondrial alterations, and enhances parasite survival, in monensin-exposed parasites, although it does not block other monensin-induced effects on the parasites, such as late S-phase cell cycle arrest. Monensin does not induce autophagy in a parasite strain deficient in the mitochondrial DNA repair enzyme TgMSH-1 an enzyme that mediates monensin-induced late S-phase arrest. TgMSH-1 therefore either mediates cell cycle arrest and autophagy independently, or autophagy occurs downstream of cell cycle arrest in a manner analogous to apoptosis of cells arrested in G2 of the cell cycle. Overall, our results point to autophagy as a potentially important mode of cell death of protozoan parasites in response to antimicrobial drugs and indicate that disruption of the autophagy pathway could result in drug resistance.

Original languageEnglish (US)
Article numbere42107
JournalPLoS One
Volume7
Issue number7
DOIs
StatePublished - Jul 25 2012

Fingerprint

Monensin
autophagy
monensin
Autophagy
Toxoplasma
Toxoplasma gondii
Parasites
death
drugs
parasites
Pharmaceutical Preparations
Cells
Cell Cycle Checkpoints
Cell death
S Phase
interphase
cell death
Cell Death
DNA Repair Enzymes
anti-infective agents

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Analysis of monensin sensitivity in toxoplasma gondii reveals autophagy as a mechanism for drug induced death. / Lavine, Mark D.; Arrizabalaga, Gustavo.

In: PLoS One, Vol. 7, No. 7, e42107, 25.07.2012.

Research output: Contribution to journalArticle

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