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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.

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