Defining novel susceptibility mechanisms to low virulence Toxoplasma gondii strains using the Collaborative Cross and parasite genetics

PROJECT SUMMARY Toxoplasma gondii is a widespread intracellular parasite of warm-blooded animals and causative agent of human toxoplasmosis. Mus musculus is an important intermediate host that is possibly entangled in an evolutionary arms race with this apicomplexan parasite. Our current work using forward genetics to understand mechanisms of resistance to T. gondii suggests that susceptibility to primary infection is genetically determined. In this grant submission, we propose to leverage a high diversity recombinant inbred mouse panel, the Collaborative Cross (CC), as well as parasite genetics to dissect mechanisms that determine disease outcome following primary infection. Our preliminary data predicts that novel alleles segregating within the CC panel will determine host susceptibility to previously described `less virulent' strains of T. gondii. However, virulence is relative and determined by the combined genetics of parasite and host, but which genes and host responses drive disease severity are not fully understood. We hypothesize that novel host-parasite interactions govern disease outcome following Toxoplasma gondii infection in Mus musculus castaneus and musculus murine subspecies. Approaches from genetics, molecular parasitology and immunology will be utilized to evaluate these hypotheses. In Aim 1, we propose to use the entire CC panel to genetically map and identify host susceptibility genes to parasite infection with a `low virulent' strain of T. gondii. In Aim 2, we will leverage our unpublished data to interrogate a parasite locus associated with host morbidity following primary infection in non-laboratory mice. Whether a genetic conflict occurs between host and parasite genes identified in this proposal will be examined. With the overarching goal of preventing human toxoplasmosis, insights gained from this proposal will guide future research on host-parasite relationships and the genetic basis of parasitic disease.