The ratToxo1locus 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.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...

Epidemiology of and Diagnostic Strategies for Toxoplasmosis

“…Different host species are more or less susceptible. The genetic background of a given species, as demonstrated for different mouse or rat strains, may also influence the expression of virulence (51).…”

ALOX12 in Human Toxoplasmosis

“…Reciprocal LEW ϫ BN lines congenic for Toxo1 have allowed for the mapping of the genes responsible for the robust resistance phenotype to a region on rat chromosome 10 (4). These studies further demonstrated the central role played by macrophages in the immune defense against T. gondii, known for humans (5) and clearly seen in rat macrophages (3,4).…”

“…Recently, a region of the rat genome, named Toxo1, has been shown to be associated with resistance to T. gondii (3,4). Compared to rats of the susceptible Brown Norway (BN) strain, LEW (Lewis) strain rats are extremely resistant to T. gondii infection: few to no parasites are found postinoculation, very few encysted bradyzoites are found, no antibody is produced, and there is no transmission to their pups.…”

Cancer in the parasitic protozoans Trypanosoma brucei and Toxoplasma gondii

“…In some cases, both the host and the parasite die when an animal host is infected with the RH strain. For example, mice will die very quickly when they are infected with the RH strain without any treatment whereas rats can survive without any observed clinical signs because the RH strain is unable to grow in these animals due to innate immunity (77)(78)(79).…”