title: The rat Toxo1 locus directs toxoplasmosis outcome and controls parasite proliferation and spreading by macrophage-dependent mechanisms.
abstract: Toxoplasmosis is a healthcare problem in pregnant women and immunocompromised patients. Like humans, rats usually develop a subclinical chronic infection. LEW rats exhibit total resistance to Toxoplasma gondii infection, which is expressed in a dominant mode. A genome-wide search carried out in a cohort of F(2) progeny of susceptible BN and resistant LEW rats led to identify on chromosome 10 a major locus of control, which we called Toxo1. Using reciprocal BN and LEW lines congenic for chromosome 10 genomic regions from the other strain, Toxo1 was found to govern the issue of T. gondii infection whatever the remaining genome. Analyzes of rats characterized by genomic recombination within Toxo1, reduced the interval down to a 1.7-cM region syntenic to human 17p13. In vitro studies showed that the Toxo1-mediated refractoriness to T. gondii infection is associated with the ability of the macrophage to impede the proliferation of the parasite within the parasitophorous vacuole. In contrast, proliferation was observed in fibroblasts whatever the genomic origin of Toxo1. Furthermore, ex vivo studies indicate that macrophage controls parasitic infection spreading by a Toxo1-mediated mechanism. This forward genetics approach should ultimately unravel a major pathway of innate resistance to toxoplasmosis and possibly to other apicomplexan parasitic diseases.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Département de Génétique, Inserm U.563, Toulouse F-31300 France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cavaillès
authors.forename: Véronique
authors.initials: V
authors.lastname: Sergent
authors.forename: Cordelia
authors.initials: C
authors.lastname: Bisanz
authors.forename: Olivier
authors.initials: O
authors.lastname: Papapietro
authors.forename: Céline
authors.initials: C
authors.lastname: Colacios
authors.forename: Magali
authors.initials: M
authors.lastname: Mas
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Subra
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagrange
authors.forename: Maryline
authors.initials: M
authors.lastname: Calise
authors.forename: Sylvie
authors.initials: S
authors.lastname: Appolinaire
authors.forename: Thomas
authors.initials: T
authors.lastname: Faraut
authors.forename: Philippe
authors.initials: P
authors.lastname: Druet
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Saoudi
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Bessieres
authors.forename: Bernard
authors.initials: B
authors.lastname: Pipy
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Cesbron-Delauw
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Fournié
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D049109:Cell Proliferation; D002874:Chromosome Mapping; D005260:Female; D005347:Fibroblasts / Q000469:parasitology; D008040:Genetic Linkage; D005819:Genetic Markers / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D007274:Injections, Intraperitoneal; D017737:Macrophages, Peritoneal / Q000469:parasitology*; D008297:Male; D018895:Microsatellite Repeats; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014122:Toxoplasma / Q000254:growth & development / Q000502:physiology*; D014124:Toxoplasmosis, Animal / Q000235:genetics* / Q000469:parasitology / Q000473:pathology
chemical_list: D005819:Genetic Markers