Host metabolism regulates growth and differentiation of Toxoplasma gondii

Dina R. Weilhammer, Anthony T. Iavarone, Eric N. Villegas, George A. Brooks, Anthony P. Sinai, William C. Sha

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

A critical step in the pathogenesis of Toxoplasma gondii is conversion from the fast-replicating tachyzoite form experienced during acute infection to the slow-replicating bradyzoite form that establishes long-lived tissue cysts during chronic infection. Bradyzoite cyst development exhibits a clear tissue tropism in vivo, yet conditions of the host cell environment that influence this tropism remain unclear. Using an in vitro assay of bradyzoite conversion, we have found that cell types differ dramatically in the ability to facilitate differentiation of tachyzoites into bradyzoites. Characterization of cell types that were either resistant or permissive for conversion revealed that resistant cell lines release low molecular weight metabolites that could support tachyzoite growth under metabolic stress conditions and thereby inhibit bradyzoite formation in permissive cells. Biochemical analysis revealed that the glycolytic metabolite lactate is an inhibitory component of supernatants from resistant cells. Furthermore, upregulation of glycolysis in permissive cells through the addition of glucose or by overexpression of the host kinase, Akt, was sufficient to convert cells from a permissive to a resistant phenotype. These results suggest that the metabolic state of the host cell may play a role in determining the predilection of the parasite to switch from the tachyzoite to bradyzoite form.

Original languageEnglish
Pages (from-to)947-959
Number of pages13
JournalInternational Journal for Parasitology
Volume42
Issue number10
DOIs
StatePublished - Sep 2012

Bibliographical note

Funding Information:
This work was supported by NIH Grant R01AI057532 . We thank David Roos and Florence Dzierszinski (University of Pennsylvania, Philadelphia, Pennsylvania, USA) for generous gifts of Pru T.gondii reporter strains, Mark Schlissel (University of California, Berkeley, Berkeley, CA USA) for the myrAKT cDNA and Akt VIII inhibitor, and Ellen Robey (University of California, Berkeley) for comments on the manuscript.

Keywords

  • Akt
  • Bradyzoite differentiation
  • Glycolysis
  • Metabolism
  • Toxoplasma gondii

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

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