Phosphatidylthreonine and Lipid-Mediated Control of Parasite Virulence

Ruben D Arroyo-Olarte; Jos F Brouwers; Arunakar Kuchipudi; J Bernd Helms; Aindrila Biswas; Ildiko R Dunay; Richard Lucius; Nishith Gupta

doi:10.1371/journal.pbio.1002288

Phosphatidylthreonine and Lipid-Mediated Control of Parasite Virulence

PLoS Biol. 2015 Nov 13;13(11):e1002288. doi: 10.1371/journal.pbio.1002288. eCollection 2015.

Authors

Ruben D Arroyo-Olarte¹, Jos F Brouwers², Arunakar Kuchipudi¹, J Bernd Helms², Aindrila Biswas³, Ildiko R Dunay³, Richard Lucius¹, Nishith Gupta^{1

4}

Affiliations

¹ Department of Molecular Parasitology, Humboldt University, Berlin, Germany.
² Department of Biochemistry and Cell Biology, Institute of Biomembranes, Utrecht University, The Netherlands.
³ Institute of Medical Microbiology, Otto von Guericke University, Magdeburg, Germany.
⁴ Parasitology Unit, Max-Planck Institute for Infection Biology, Berlin, Germany.

Abstract

The major membrane phospholipid classes, described thus far, include phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylserine (PtdSer), and phosphatidylinositol (PtdIns). Here, we demonstrate the natural occurrence and genetic origin of an exclusive and rather abundant lipid, phosphatidylthreonine (PtdThr), in a common eukaryotic model parasite, Toxoplasma gondii. The parasite expresses a novel enzyme PtdThr synthase (TgPTS) to produce this lipid in its endoplasmic reticulum. Genetic disruption of TgPTS abrogates de novo synthesis of PtdThr and impairs the lytic cycle and virulence of T. gondii. The observed phenotype is caused by a reduced gliding motility, which blights the parasite egress and ensuing host cell invasion. Notably, the PTS mutant can prevent acute as well as yet-incurable chronic toxoplasmosis in a mouse model, which endorses its potential clinical utility as a metabolically attenuated vaccine. Together, the work also illustrates the functional speciation of two evolutionarily related membrane phospholipids, i.e., PtdThr and PtdSer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / immunology
Brain / parasitology
Brain / pathology
Cells, Cultured
Endoplasmic Reticulum / enzymology*
Endoplasmic Reticulum / metabolism
Glycerophospholipids / metabolism*
Humans
Mice
Molecular Sequence Data
Mutation
Organisms, Genetically Modified / immunology
Organisms, Genetically Modified / metabolism
Parasite Encystment
Peptide Fragments / chemistry
Peptide Fragments / genetics
Peptide Fragments / metabolism
Protein Interaction Domains and Motifs
Protozoan Proteins / chemistry
Protozoan Proteins / genetics
Protozoan Proteins / metabolism*
Protozoan Vaccines / therapeutic use
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Skin / cytology
Skin / immunology
Skin / metabolism
Skin / parasitology
Threonine / analogs & derivatives*
Threonine / metabolism
Toxoplasma / genetics
Toxoplasma / immunology
Toxoplasma / pathogenicity
Toxoplasma / physiology*
Toxoplasmosis / immunology
Toxoplasmosis / parasitology
Toxoplasmosis / pathology
Toxoplasmosis / prevention & control
Transferases (Other Substituted Phosphate Groups) / chemistry
Transferases (Other Substituted Phosphate Groups) / genetics
Transferases (Other Substituted Phosphate Groups) / metabolism*
Vaccines, Attenuated / therapeutic use
Virulence

Substances

Glycerophospholipids
Peptide Fragments
Protozoan Proteins
Protozoan Vaccines
Recombinant Fusion Proteins
Vaccines, Attenuated
phosphatidylthreonine
Threonine
Transferases (Other Substituted Phosphate Groups)

Associated data

Dryad/10.5061/dryad.564SC
GENBANK/KJ026547
GENBANK/KJ026548

Grants and funding

This work was funded by three research grants to NG (SFB618/C7, GU1100/3-1, GU1100/4-1) from the German Research Foundation (DFG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.