Efficient invasion by Toxoplasma depends on the subversion of host protein networks

Nat Microbiol. 2017 Oct;2(10):1358-1366. doi: 10.1038/s41564-017-0018-1. Epub 2017 Aug 28.

Abstract

Apicomplexan parasites are important pathogens of humans and domestic animals, including Plasmodium species (the agents of malaria) and Toxoplasma gondii, which is responsible for toxoplasmosis. They replicate within the cells of their animal hosts, to which they gain access using a unique parasite-driven invasion process. At the core of the invasion machine is a structure at the interface between the invading parasite and host cell called the moving junction (MJ) 1 . The MJ serves as both a molecular doorway to the host cell and an anchor point enabling the parasite to engage its motility machinery to drive the penetration of the host cell 2 , ultimately yielding a protective vacuole 3 . The MJ is established through self-assembly of parasite proteins at the parasite-host interface 4 . However, it is unknown whether host proteins are subverted for MJ formation. Here, we show that Toxoplasma parasite rhoptry neck proteins (RON2, RON4 and RON5) cooperate to actively recruit the host CIN85, CD2AP and the ESCRT-I components ALIX and TSG101 to the MJ during invasion. We map the interactions in detail and demonstrate that the parasite mimics and subverts conserved binding interfaces with remarkable specificity. Parasite mutants unable to recruit these host proteins show inefficient host cell invasion in culture and attenuated virulence in mice. This study reveals molecular mechanisms by which parasites subvert widely conserved host machinery to force highly efficient host cell access.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Calcium-Binding Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Female
  • Gene Expression
  • Genetic Vectors
  • HeLa Cells
  • Host-Parasite Interactions / physiology*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Organisms, Genetically Modified
  • Point Mutation
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Recombinant Proteins
  • Sf9 Cells
  • Toxoplasma / genetics
  • Toxoplasma / metabolism*
  • Toxoplasma / pathogenicity*
  • Toxoplasmosis / metabolism*
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CD2-associated protein
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • PDCD6IP protein, human
  • Protozoan Proteins
  • RON4 protein, Toxoplasma gondii
  • Recombinant Proteins
  • SH3KBP1 protein, human
  • Transcription Factors
  • Tsg101 protein
  • rhoptry neck protein 2, Toxoplasma gondii