Journal Article

A Highly Conserved Toxo1 Haplotype Directs Resistance to Toxoplasmosis and Its Associated Caspase-1 Dependent Killing of Parasite and Host Macrophage

Papapietro, Olivier, Loeuillet, Corinne, Bastien, Olivier, Cavailles, Pierre, Fournié, Gilbert J., Flori, Pierre, Lagrange, Dominique, Massera, Céline, Jublot, Delphine, Touquet, Bastien, Pilloux, Ludovic, Aldebert, Delphine, Bisanz, Cordelia, Cesbron-Delauw, Marie France, Cristinelli, Sara

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptor Proteins, Signal Transducing - metabolism / Animals / Apoptosis / Apoptosis Regulatory Proteins - metabolism / Biology and Life Sciences / Caspase 1 - genetics / Caspase 1 - metabolism / Caspase Inhibitors - pharmacology / Cell Death - drug effects / Cell Death - genetics / Chromosomes / Enzyme Activation - drug effects / Enzyme Activation - genetics / Experiments / Gene expression / Genetic Loci / Haplotypes / Health aspects / Host-parasite relationships / Humans / Infections / Inflammasomes - genetics / Inflammasomes - metabolism / Interleukin-1beta - genetics / Interleukin-1beta - metabolism / Life Sciences / Macrophages / Macrophages, Peritoneal - metabolism / Macrophages, Peritoneal - parasitology / Macrophages, Peritoneal - pathology / Medicine and Health Sciences / Mice / Microbiological research / Microbiology and Parasitology / Oligopeptides - pharmacology / Parasites / Rats / Research and Analysis Methods / Rodents / Studies / Toxoplasma / Toxoplasma - metabolism / Toxoplasmosis - genetics / Toxoplasmosis - metabolism / Toxoplasmosis - pathology