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.
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Pierre
P
Cavailles
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; GIMAP, EA 3064, Saint-Etienne, France.
Pierre
P
Flori
UMR Inserm, U1043, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
Olivier
O
Papapietro
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Cordelia
C
Bisanz
UMR Inserm, U1043, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
Dominique
D
Lagrange
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Ludovic
L
Pilloux
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Céline
C
Massera
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Sara
S
Cristinelli
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Delphine
D
Jublot
UMR 5168, CNRS/INRA, Université Joseph Fourier, CEA, Grenoble, France.
Olivier
O
Bastien
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Corinne
C
Loeuillet
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Delphine
D
Aldebert
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Bastien
B
Touquet
UMR Inserm, U1043, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
Gilbert J
GJ
Fournié
UMR 5163, Centre National de la Recherche Scientifique (CNRS), Grenoble, France; Université Grenoble 1, Grenoble, France.
Marie France
MF
Cesbron-Delauw
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D056426:Genetic Loci; D006239:Haplotypes; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D014122:Toxoplasma / Q000378:metabolism*; D014123:Toxoplasmosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; C529636:NALP1 protein, mouse; D009842:Oligopeptides; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D020170:Caspase 1