The coccidian parasites Toxoplasma and Neospora dysregulate mammalian lipid droplet biogenesis

J Biol Chem. 2017 Jun 30;292(26):11009-11020. doi: 10.1074/jbc.M116.768176. Epub 2017 May 9.

Abstract

Upon infection, the intracellular parasite Toxoplasma gondii co-opts critical functions of its host cell to avoid immune clearance and gain access to nutritional resources. One route by which Toxoplasma co-opts its host cell is through hijacking host organelles, many of which have roles in immunomodulation. Here we demonstrate that Toxoplasma infection results in increased biogenesis of host lipid droplets through rewiring of multiple components of host neutral lipid metabolism. These metabolic changes cause increased responsiveness of host cells to free fatty acid, leading to a radical increase in the esterification of free fatty acids into triacylglycerol. We identified c-Jun kinase and mammalian target of rapamycin (mTOR) as components of two distinct host signaling pathways that modulate the parasite-induced lipid droplet accumulation. We also found that, unlike many host processes dysregulated during Toxoplasma infection, the induction of lipid droplet generation is conserved not only during infection with genetically diverse Toxoplasma strains but also with Neospora caninum, which is closely related to Toxoplasma but has a restricted host range and uses different effector proteins to alter host signaling. Finally, by showing that a Toxoplasma strain deficient in exporting a specific class of effectors is unable to induce lipid droplet accumulation, we demonstrate that the parasite plays an active role in this process. These results indicate that, despite their different host ranges, Toxoplasma and Neospora use a conserved mechanism to co-opt these host organelles, which suggests that lipid droplets play a critical role at the coccidian host-pathogen interface.

Keywords: Toxoplasma gondii; host-pathogen interaction; lipid droplet; lipid metabolism; parasite.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Fibroblasts / metabolism*
  • Fibroblasts / parasitology
  • Fibroblasts / pathology
  • Host-Parasite Interactions / physiology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipid Droplets / metabolism*
  • Lipid Droplets / parasitology
  • Lipid Droplets / pathology
  • Neospora / physiology*
  • TOR Serine-Threonine Kinases / metabolism
  • Toxoplasma / physiology*
  • Toxoplasmosis / metabolism*
  • Toxoplasmosis / pathology

Substances

  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases