The Rat Toxo1 Locus Directs Toxoplasmosis Outcome and Controls Parasite Proliferation and Spreading by Macrophage-Dependent Mechanisms

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 F₂ progeny of susceptible BN and resistant LEW rats led to identify on chromosome 10 a major locus of control, which we called Toxol. Using reciprocal BN and LEW lines congenic for chromosome 10 genomic regions from the other strain, Toxo 1 was found to govern the issue of T. gondii infection whatever the remaining genome. Analyzes of rats characterized by genomic recombination within Toxol, reduced the interval down to a 1.7-cM region syntenic to human 17p13. In vitro studies showed that the Toxol-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 Toxol. Furthermore, ex vivo studies indicate that macrophage controls parasitic infection spreading by a Toxol-mediated mechanism. This forward genetics approach should ultimately unravel a major pathway of innate resistance to toxoplasmosis and possibly to other apicomplexan parasitic diseases.