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

<div><p>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 <i>Toxo1</i> locus that directs toxoplasmosis outcome and controls parasite spreading by a macrophage-dependent mechanism. Now, we narrowed down <i>Toxo1</i> to a 891 kb interval containing 29 genes syntenic to human 17p13 region. Strikingly, <i>Toxo1</i> is included in a haplotype block strictly conserved among all refractory rat strains. The sequencing of <i>Toxo1</i> 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 <i>Toxo1</i>, and highlighting the NOD-like receptor, <i>Nlrp1a</i>, 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 <i>Toxo1</i>-dependent refractoriness <i>in vivo</i> correlated with both the ability of macrophages to restrict <i>T. gondii</i> growth and a <i>T. gondii</i>-induced death of intracellular parasites and its host macrophages. The parasite-induced cell death of infected macrophages bearing the LEW-<i>Toxo1</i> 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 <i>Toxo1</i>-dependent response of rat macrophages to <i>T. gondii</i> 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.</p>