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

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. © 2014 cavailles et al.