Identifying host genes that determine disease outcome to Toxoplasma infection through expression QTL analysis (164.23)

Abstract

Abstract Disease outcome is significantly influenced by one’s genetic background. Here we explore the genetic basis for differences in host susceptibility to infection with Toxoplasma, an orally acquired parasite that chronically infects 2 billion people worldwide. The survival of 30 recombinant inbred (RI) mouse strains, derived from crosses between susceptible C57BL/6 and resistant A/J mice, following oral challenge with Toxoplasma has previously been reported and genetic loci on mouse chromosomes 1, 9, 11 and 15 control susceptibility. However, it is not clear what genes within these loci predispose B6 mice to infection. To identify genes within these loci that determine disease outcome, we sequenced the RNA of bone marrow derived macrophages from each RI mouse strain after Toxoplasma infection or TNFα + IFNγ stimulation. The macrophage cell type was chosen because it elicits many of the host’s immuno-regulatory and toxoplasmacidal mechanisms following oral infection and/or cytokine stimulation. The gene expression of each gene was considered a quantitative trait (expression QTL) that was subsequently mapped to mouse genetic loci. By analyzing both trans- and cis-regulation of gene expression, key regulators of the macrophage response to cytokine stimulation was uncovered, including the differential expression of a single candidate gene that correlates well with host susceptibility loci on mouse chromosomes 3, 9 and 15. Results from ongoing experiments will be discussed.