A highly conserved Toxo1 haplotype directs resistance to toxoplasmosis and its associated caspase-1 dependent killing of parasite and host macrophage

PLoS Pathog. 2014 Apr 3;10(4):e1004005. doi: 10.1371/journal.ppat.1004005. eCollection 2014 Apr.

Abstract

Natural immunity or resistance to pathogens most often relies on the genetic make-up of the host. In a LEW rat model of refractoriness to toxoplasmosis, we previously identified on chromosome 10 the Toxo1 locus that directs toxoplasmosis outcome and controls parasite spreading by a macrophage-dependent mechanism. Now, we narrowed down Toxo1 to a 891 kb interval containing 29 genes syntenic to human 17p13 region. Strikingly, Toxo1 is included in a haplotype block strictly conserved among all refractory rat strains. The sequencing of Toxo1 in nine rat strains (5 refractory and 4 susceptible) revealed resistant-restricted conserved polymorphisms displaying a distribution gradient that peaks at the bottom border of Toxo1, and highlighting the NOD-like receptor, Nlrp1a, as a major candidate. The Nlrp1 inflammasome is known to trigger, upon pathogen intracellular sensing, pyroptosis programmed-cell death involving caspase-1 activation and cleavage of IL-1β. Functional studies demonstrated that the Toxo1-dependent refractoriness in vivo correlated with both the ability of macrophages to restrict T. gondii growth and a T. gondii-induced death of intracellular parasites and its host macrophages. The parasite-induced cell death of infected macrophages bearing the LEW-Toxo1 alleles was found to exhibit pyroptosis-like features with ROS production, the activation of caspase-1 and IL1-β secretion. The pharmacological inactivation of caspase-1 using YVAD and Z-VAD inhibitors prevented the death of both intravacuolar parasites and host non-permissive macrophages but failed to restore parasite proliferation. These findings demonstrated that the Toxo1-dependent response of rat macrophages to T. gondii infection may trigger two pathways leading to the control of parasite proliferation and the death of parasites and host macrophages. The NOD-like receptor NLRP1a/Caspase-1 pathway is the best candidate to mediate the parasite-induced cell death. These data represent new insights towards the identification of a major pathway of innate resistance to toxoplasmosis and the prediction of individual resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Caspase Inhibitors / pharmacology
  • Cell Death / drug effects
  • Cell Death / genetics
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Genetic Loci*
  • Haplotypes*
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / metabolism
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Macrophages, Peritoneal / metabolism*
  • Macrophages, Peritoneal / parasitology
  • Macrophages, Peritoneal / pathology
  • Mice
  • Oligopeptides / pharmacology
  • Rats
  • Toxoplasma / metabolism*
  • Toxoplasmosis / genetics
  • Toxoplasmosis / metabolism*
  • Toxoplasmosis / pathology

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Caspase Inhibitors
  • IL1B protein, human
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • NALP1 protein, mouse
  • Oligopeptides
  • benzyloxycarbonyl-valyl-alanyl-aspartic acid
  • Caspase 1

Grant support

This work was supported by the ANR grants N° 05-MIIM-020-02 and N° 07-MIME-013-01, and the Lyonbiopole competitiveness cluster. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.