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.T he protozoan Toxoplasma gondii is an obligate intracellular parasite that infects humans and a broad spectrum of vertebrate hosts. It is found worldwide, and the infection is common as indicated by a high prevalence of specific Ab among almost all human populations. T. gondii infection occurs by oral ingestion of either cysts from infected animal tissues, or oocysts excreted by cats. In healthy individuals, T. gondii establishes a chronic asymptomatic infection characterized by a specific immune response and the encystment of dormant bradyzoites into host tissues. A serious threat to human health can occur under congenital infection or reactivation of a latent infection in immunodeficient patients (1).Epidemiological studies have indicated that the genetic make-up of the host and of the parasite are involved in the phenotypic expression of toxoplasmosis (2-4). Genetic studies in humans are hampered by both population heterogeneity and environment variability. In experimental conditions, genetic and environmental factors are under control. Results from genetic studies in animal models can be applied to human pathology through comparative genomics (5, 6). Rats, like humans, usually develop subclinical toxoplasmosis (7); this contrasts with the severity of the disease developed in most strains of mice. Surprisingly, the LEW rat strain exhibits a complete resistance to Toxoplasma infection (8). Indeed, unlike susceptible BN and F344 rats, LEW rats do not show trace of parasitic infection as shown by negative serology and lack of brain cysts. F 1 hybrid (LEW ϫ BN) and (LEW ϫ F344) rats are resistant to T. gondii, indicating a dominant effect of the involved gene(s) (9). W...
Toxoplasmosis is a ubiquitous parasitic infection causing a wide spectrum of diseases. It is usually asymptomatic but can lead to severe ocular and neurological disorders. Among the small-animal models available to study factors that determine susceptibility to toxoplasmosis, the rat appears to be rather similar to humans, particularly in terms of resistance to acute infection. Here, we demonstrate that the Lewis (LEW) rat strain displays an unexpected refractoriness to Toxoplasma infection. Complete resistance was assessed by both negative anti-Toxoplasma serology and lack of detection of the parasite during the course of infection. In this model, sex, age, major histocompatibility complex, and inoculum size had no effect on resistance. Interestingly, progeny from F 1 hybrid crosses between Fischer (F344) or Brown Norway susceptible rats and LEW resistant rats were also fully resistant, showing a dominant effect of the gene or set of genes. Furthermore, resistance of the LEW rat was shown to be dependent on hematopoietic cells and partially abrogated by neutralization of endogenous gamma interferon. To our knowledge, this is the first observation of a rodent strain that is refractory to Toxoplasma infection. This model is therefore an attractive and powerful tool to dissect host genetic factors involved in susceptibility to toxoplasmosis.Toxoplasma gondii is an obligate, intracellular parasite which can infect all mammals, including humans. In natural oral infection, the parasite initially crosses the intestinal barrier and disseminates, during the acute disease, as replicating cytolytic tachyzoites. The development of a vigorous immune response leads to a chronic infection characterized by the persistence of encysted parasites within the host's muscular and nervous tissues.In the human population, toxoplasmosis is usually asymptomatic, and substantial morbidity and mortality are most often found in immunocompromised patients (e.g., in those with AIDS, with organ transplants, or who received anticancer therapies) and in congenitally infected infants (10). Despite the fact that the host immunologic status is known to be critical in the outcome of Toxoplasma infection (7, 12), the severity of the disease caused by Toxoplasma infection varies widely depending on the host species (8, 30, 33) and remains unpredictable among individuals.Up to now, genetic studies on susceptibility to toxoplasmosis have been confined to the mouse model (2, 3, 23). A limitation of this model is the high susceptibility of certain strains of mice to toxoplasmosis, with a high rate of mortality during acute infection. Interestingly, in respect to clinical course and in utero transmission, toxoplasmoses in rats and humans are similar, and the infection in rats can serve as a model for human toxoplasmosis (6,26,(33)(34)(35). Hence, like humans, rats do not succumb to acute toxoplasmosis even with a high inoculum of Toxoplasma strains that are highly virulent in mice. In a comparative study using various strains of rats, we have previously s...
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