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To be or not to be … resistant to Toxoplasma gondii

Vendredi 12 décembre 2014 14:00 - Duree : 1 heure
Lieu : Institut Jean Roget Salle de Conférence, 5ème Etage Campus Santé 38700 La Tronche

Orateur : Pierre CAVAILLES (LAPM, CNRS UMR 5163, UJF, Grenoble)

Natural immunity or resistance to pathogens most often relies on the genetic make-up of the host. Results from genetic studies in animal models can be applied to human pathology through comparative genomics. We demonstrated that the rat appears to be rather similar to humans, particularly in terms of resistance to acute infection, and that the Lewis (LEW) rat strain displays an unexpected refractoriness to Toxoplasma infection. A genome-wide search carried out in a cohort of F2 progeny of susceptible BN and resistant LEW rats led to identify on chromosome 10 the Toxo1 locus that directs toxoplasmosis outcome and controls parasite spreading by a macrophage-dependent mechanism. Firstly, by genetic dissection in a set of BN-LEW reciprocal congenic lines and by haplotype mapping of five refractory and four susceptible strains, we narrowed down Toxo1 to an 891 kb interval containing 29 genes syntenic to human 17p13. Toxo1 was shown to be included in a haplotypic block strictly conserved among five refractory rat strains. The sequencing of Toxo1 in the nine rat strains showed conserved polymorphisms restricted to resistant rat strains and displaying a distribution gradient that peaks at the bottom border of Toxo1, with the NOD-like receptor Nlrp1a as a major candidate. Secondly, by functional studies we 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 as well as its host macrophages. The parasite-induced cell death of infected macrophages bearing the LEW-Toxo1 alleles was found to exhibit pyroptosis-like characteristics. The pharmacological inactivation of the Nlrp1a pathway prevented the death of both intravacuolar parasites and host non-permissive macrophages but failed to restore parasite proliferation. These finding 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 both 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 may lead to the prediction of individual resistance.

Contact : cordelia.bisanz@ujf-grenoble.fr

Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (Institut Jean Roget)
Nature évènement : (Séminaire)
Evènement répétitif : (Séminaire IJR)
Site de l'évènement : Pôle Santé / La Tronche

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